Thieno[2,3-d]oxazines

ABSTRACT

2-Aminothiophene-3-carboxamides are converted to oxamates or fumaramides by acylation of the amino group. Cyclization yields thieno[2,3-d]pyrimidines which may also be prepared from the corresponding oxazines. Compounds illustrative of those having inhibitory action on the immediate hypersensitivity reaction in mammals are N-[3-(aminocarbonyl)-4,5,6,7-tetrahydrobenzo[b]thien-2-yl]oxamic acid, ethyl 5,6,7,8-tetrahydro-4-oxo-4H-benzothieno[2,3-d][1,3]oxazine-2-carboxylate, and ethyl 3,4-dihydro-6-ethyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylate.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 826,591 Sept. 10,1975, now U.S. Pat. No. 4,159,377 patented June 26, 1979 which is acontinuation-in-part of application Ser. No. 611,955 filed Sept. 10,1975 and now U.S. Pat. No. 4,054,656 patented Oct. 18, 1977. Thedisclosure herein is identical with that of Ser. No. 611,955 except forthat following Procedure 82.

FIELD OF THE INVENTION

This invention involves a novel series of pyrimidine compounds having afused thiophene ring, namely a series of thieno[2,3-d]pyrimidines, andthe structurally related thieno-oxazines, and thienylamides which areintermediates in the synthesis of the pyrimidines. It also relates totherapeutic methods and compositions employing one of thethieno[2,3-d]pyrimidines, thieno-oxazines, or thienyloxamates as theactive ingredient.

DESCRIPTION OF THE PRIOR ART

The literature most closely related to the subject of this invention isrepresented by the 1971, references.

1. West German patent application No. 2,104,435 published Aug. 26, 1971,"New Benzothienopyrimidine Derivatives, Procedure for Their Preparationand Their Application in Pharmaceutics."

2. Sauter, et al., Monatsh. 105, 558-562 (1974), "Synthesis of BasicallySubstituted [1]Benzothieno[2,3-d]pyrimidine Derivatives . . . "

3. Sauter, et al., Monatsh. 105, 1258-1265 (1974), "CyclizationReactions to Thiazolo[2,3-a]thieno[2,3-d]pyrimidines."

4. Robba, et al., Bull. Soc. Chim. France, (1974) 2864-2870, "No. 562.-Thienopyrimidines. IV.- Synthesis and Study of Derivatives of ThiopheneAmino Acids and Aminoketones."

5. Wright, et al., J. Med. Chem. 16, 861-2 (1973), "AntiasthmaAgents. 1. 4-Oxo-4H-[1]benzothieno[2,3-b]pyran-2-carboxylic Acid and4-Oxo-4H-[1]benzofuro[3,2-b]pyran-2-carboxylic Acid."

6. Hall, et al., J. Med. Chem. 17, 685-690 (1974), "QuinolineDerivatives as Antiallergy Agents."

7. Barth, U.S. Pat. No. 3,883,653 (May 13, 1975). Method of PreventingAsthmatic Symptoms.

8. Sellstedt, et al., U.S. Pat. No. 3,888,858 (June 10, 1975).3,4-Dihydro-4-oxo-2-quinazolinecarboxyic Acids, Salts and Esters asAnti-allergic Agents.

9. Narr, et al., U.S. Pat. No. 3,888,851 (June 10, 1975).2,4-Diamino-Substituted Thieno[3,2-b]pyrimidines and Salts Thereof.

10. Baetz, U.S. Pat. No. 3,888,983 (June 10, 1975). Derivatives ofThazolino-pyrimidin-6-ones, In Inducing Analgesia.

11. McClelland, et al., J. Chem. Soc. 78-81 (1948). "Some 1:3-OxazineDerivatives of Thionaphthen."

12. Tinney, et al., J. Med. Chem. 17, 624-630 (1974). "Synthesis andPharmacological Evaluation of2,3-Dihydro-1H-thieno[2,3-e][1,4]diazepines.

References 1, 2, and 3 refer to various thieno[2,3-d]pyrimidines, butthese substances are distinguished by the nature of the substituents inthe 2-position and the lack of disclosure of anti-allergic utility.

Reference 4 refers to 2-aminothiophene-3-carboxylates and -carboxamidesuseful for preparing thieno[2,3-d]pyrimidines.

References 5, 6, 7, and 8 involve heterocyclic organic compounds havinganti-allergic activity of the type with which the present invention isconcerned but these substances involve different heterocyclic ringsystems than the thieno[2,3-d]pyrimidines of the present invention.

References 9, 10, and 11 involve pyrimidine compounds having a thiophenering fused thereto, but they too represent different heterocyclicsystems from those with which the present invention is concerned, anddifferent medical utilities.

Reference 12 refers to hexahydrobenzothieno[2,3-e][1,4]diazepin-2-oneswhich were synthesized for evaluation as anti-anxiety agents.

SUMMARY OF THE INVENTION

This invention provides compounds of Formulas I, IV and V ##STR1##

These substances are useful in the treatment of diseases of allergy andparticularly asthma, hay fever, and food allergy which are characterizedby episodes of acute attack provoked by inhalation or ingestion of anallergen. The compounds have the advantage for chronic prophylactic useof being substantially free of other pharmacologic activity, and theyhave low toxicities. Preferred members are orally active.

The compounds of Formulas IV and V are also useful as intermediates forthe manufacture of the compounds of Formula I.

In Formula I, the symbol R² refers to a carboxylic acid substituent or alower alkyl ester or nontoxic pharmacologically inert metal saltthereof. It also refers to the vinylogous carboxylic acids, esters, andsalts in which R² is the substituent of CH═CHCO₂ R³ and which R³ ishydrogen, lower alkyl having 1-8 carbon atoms, or a nontoxicpharmacologically inert metal cation. By nontoxic pharmacologicallyinert is meant that the cation in the doses required for theadministration of one of the salts containing it is without deliteriouseffect or interfering pharmacologically action on the host. Suitablemetal cations are preferably the alkali metals sodium and potassium, butalso other nontoxic pharmacologically inert cations such as calcium,magnesium, aluminum, zinc, and barium. R² may also be the methylol groupor the formate, or a lower alkyl ester thereof. R² may also be thecarboxaldehyde, 5-tetrazolyl, or N-(tetrazol-5-yl)carbamyl group. To sumup, R² is a group having one of the following formulas in which R³ hasthe meaning given above, and R is lower alkyl having 1 to 8 carbonatoms. ##STR2## In Formula I, R³ is the same as above, and R⁵ and R⁶ maybe hydrogen, lower alkyl having from 1 to 8 carbon atoms, lower alkenylhaving from 3 to 6 carbon atoms, lower alkoxy having from 1 to 6 carbonatoms, hydroxy, nitro, amino, halo including chlorine, bromine, iodine,and fluorine, phenyl, alkanoyl having from 2 to 6 carbon atoms or theyare bonded to one another to form a cycloalkene ring fused to thethiophene ring and having a total of from 5 to 7 annular ring carbonatoms or an R-substituted cycloalkene having 5 to 7 annular ring carbonatoms wherein R has the same meaning as above.

In Formula V, R³ has the same meaning as above and A is either acovalent bond linking the --CO₂ R³ group to the ring or it is the vinylgroup, --CH═CH--, joining the --CO₂ R³ group to the ring. The symbols Land B signify some of the same groups identified for R⁵ and R⁶, buttheir definition is somewhat more limited. L and B may be hydrogen,lower alkyl having from 1 to 8 carbon atoms, lower alkenyl having from 3to 6 carbon atoms, phenyl, alkanoyl having from 2 to 6 carbon atoms, orthey may be joined to form a cycloalkene ring fused to the thiophenering and having from 5 to 7 annular ring carbon atoms or R-substitutedcycloalkene having from 5 to 7 annular ring carbon atoms wherein R hasthe same meaning as above.

In Formula IV, the symbols R³, A, L and B have the same meaning as isindicated for Formula V.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formulas I, IV and V inhibit the degranulation ofsensitized mast cells. Immediate hypersensitivity reactions such asasthma, hay fever, allergic rhinitis, urticaria, and food allergy arebelieved to be mediated by reaction of immunoglobulin E, sometimesreferred to as reaginic antibody with an antigen on the cell membrane ofa mast cell to initiate reactions within the mast cell which ultimatelyrelease mediators such as bradykinin, histamine, serotonin, or slowreacting substance-A (SRS-A). The mediators effect changes in end organssuch as airways, blood vessel, skin, and mucus membranes resulting inthe symptoms of an allergic attack. The present substances are believedto prevent the release of mediators thereby preventing the allergicattack. They are, therefore, useful in the prophylactic treatment ofsubjects possessing hypersensitivities of the foregoing types, andinhibit acute allergic attacks such as an asthmatic attack. Preferredcompounds are distinguished particulary by the fact that they are orallyactive, have very low toxicities, and are substantially devoid of othertypes of pharmacologic action including antihistaminic action. Thus,they are not primarily of value in the treatment of the fulminatingallergic reactions but are of particular value for use prophylacticallyby hypersensitive subjects to prevent the manifestations of allergicreaction on exposure to an allergen for the hypersensitive condition.

Activity of test compounds in the passive cutaneous anaphylaxis reaction(PCA) in the rat has been shown in the prior art to correlate with theutility of active compounds in the treatment of immediatehypersensitivity conditions such as asthma. Rat reaginic antiserum isprepared substantially according to the method of Mota, Immunology 7,681-699 (1964) employing male Sprague-Dawley (Carworth Farms) or Wistar(Harlan) rats weighing 100-175 g. which are injected intramuscularlywith a solution of egg albumin in saline at a dose of 10 mg. per kg. andintraperitoneally with 2×10¹⁰ Bordetella pertussis organisms. Twelvedays after injection, the serum is collected and the antibody titer isdetermined. The sera are pooled which contain sufficient antibody tocause a 10 mm. spot in the dorsal skin of the rat in the PCA test afterdilution 10 fold. The highest dilution of antiserum capable of inducingPCA in the rat 48 to 72 hrs. after injection is normally in the range of50-80. The selected reaginic anti-sera are stored frozen until use.

For carrying out the test, groups of 5 to 10 male Sprague-Dawley(Carworth Farms) rats, each rat weighing 100-150 g., are used.Forty-eight hours prior to the test, the animals are passivelysensitized by intradermal injection of 0.1 ml. of diluted antiserum atvarious locations on the shaved skin of the back. A dilution ofantiserum is used so that a spot following challenge of 20-25 mm. indiameter is obtained. A higher dilution of the antiserum is injected inat least one location to allow a more sensitive measure of the activityof less potent compounds. A latent period of 48 hrs. is usually allowedbefore the animals are challenged. According to the usual screeningprocedure, 15 min. prior to challenge the test drug is administeredeither by intraperitoneal injection, intravenous injection, or orally bygavage. Challenge involves an intravenous injection of a dose of 25mg./kg. of egg albumin and 25 mg./kg. of Evans' blue dye in saline. Thedye serves simply as a marker. The response of the antigen challenge inthe localities on the skin which have been previously sensitized resultsin increased capillary permeability at the sensitized site and leakageof the blue dye into the area surrounding the sensitized site. The PCAresponse is scored by measuring the mean spot diameter on the excisedand reversed skin 20-30 min. after challange. In each experiment a groupof control animals receiving no drug is employed. The percent inhibitionof the PCA is calculated by determining the mean diameters of the spotsin the control and treated animals and computing the difference betweenthe squares of the mean diameters of the control animals and the treatedanimals and expressing this difference as a percentage of the square ofthe mean diameter of the control animals. Results are expressed aspercent inhibition.

Rats may be injected intradermally with 0.1 ml. of a solution containing1 mg./ml. histamine 10 min. prior to sacrificing. This permits adetermination of whether the test compound is exerting an antihistaminiceffect on the end organ rather than interfering with mediator releasefrom the mast cells in inhibiting the PCA.

Various doses of test compound in parallel experiments are employed whena dose response curve is to be constructed for quantitative comparisonof potencies among active compounds. The ID₅₀, the dose at which 50%inhibition of the PCA occurs, is determined by interpolation. In othermodifications, various time intervals are allowed between drug treatmentand challenge to ascertain the duration of drug effect.

A more sophisticated test reflecting the utility of the presentsubstances in the treatment of immunologically inducedbronchoconstriction involves an allergic respiratory model in the rat inwhich male Harlan rats weighing 225-275 g. each are actively sensitizedwith egg albumin and B. pertussis vaccine (2×10¹⁰ organisms per rat) asbefore for the preparation of the reaginic antisera. Thirteen to fifteendays after sensitization, the rats are prepared for intraduodenaladministration of compounds by exposure of the duodenum through a smallabdominal incision, and the jugular vein, carotid artery, and tracheaare cannulated. The jugular vein cannula is used for the administrationof the egg albumin challange and blood pressure is measured through thecannulated carotoid artery. The tracheal cannula is connected to a glassT-tube one arm of which is open to the atmosphere, and the other arm ofwhich is connected to a pressure transducer for the measurement of theinspiratory and expiratory pressure. Changes in inspiratory andexpiratory pressure are monitored as a reflection of changes in airwayresistance following challange with the egg albumin antigen. The drugsare administered intraduodenally 15 min. prior to challenge with aninjection of egg albumin and the changes in airway resistance relativeto the control animals are determined. The antigenic challenge dose isadjusted to effect an approximately 36% decrease in inspiratory andexpiratory pressure since this was found to be approximately the maximumwhich the animals can survive. The drug effect on this decrease ininspiratory and expiratory pressure is then determined for various dosesof drug. That dose which produces the half maximal response isdetermined by interpolation from a dose response curve (ID_(1/2) max.).

The data shown in the following table reflects the oral anti-allergicaction some of the substances of the present invention in the foregoingtests.

    ______________________________________                                        Oral Anti-Allergic Action In Rats                                                                  Allergic Respira-                                                 PCA Response                                                                              tory Response LD.sub.50 *                                Drug     (ID.sub.50, mg./kg.)                                                                      (ID.sub.178  max. mg./kg.)                                                                  (mg./kg.)                                  ______________________________________                                        Procedure 2                                                                            15.4        3.8           > 3160                                     Procedure 27                                                                           11.4                                                                 Procedure 28                                                                           < 5.0                                                                Procedure 29                                                                           3.1         1.0           1600-5000**                                Procedure 36                                                                           15.0                                                                 Procedure 43                                                                           6.7                                                                  Procedure 44                                                                           13.0                                                                 Procedure 53                                                                           28.0.sup.+                                                           Procedure 55                                                                           34.0.sup.+                                                           Procedure 56                                                                           28.0                                                                 ______________________________________                                         *Acute oral toxicity in the rat.                                              **LD.sub.50 is greater than 1600 mg./kg., but less than 5000 mg./kg.          .sup.+ 2 hr. interval between drug dosage and challenge.                 

Cromolyn sodium is inactive on oral administration in the foregoingtests. This substance is used clinically in the prophylatic treatment ofasthmatic patients by oral inhalation and its activity is reflected inthe foregoing rat PCA test when it is administered by the intravenous orintraperitoneal injection. An ID₅₀ of approximately 1 mg./kg. can bedemonstrated in the rat in the PCA test when cromolyn sodium isadministered intravenously simultaneously with the antigen. Similarly,the intrinsic activity of these substances of the present inventionwhich exhibit a reduced level of activity in the PCA test whenadministered by the oral route, as compared to the activity of thesubstances listed in the foregoing table, may be shown by administrationthereof to the test animal by either the intraperitoneal or intravenousroutes.

The activity of the present substances in interfering with the releaseof allergic mediator substances may be demonstrated in vitro by a testinvolving antagonism of antigen-induced histamine release from passivelysensitized rat peritoneal mast cells. The method employed is similar tothat described by Kusner, et al., Journal of Pharmacology andExperimental Therapeutics 184, 41-46 (1973). The test involves isolationof mast cells from the rat by lavage of the peritoneal cavity andisolation of the cellular material from the lavage fluid. The cells aresensitized by shaking in antiserum from rats sensitized as describedabove with respect to the passive cutaneous anaphylaxis test. Thesensitized cells are then exposed to the egg albumin antigen and therelease of histamine from the cells is measured by an automatedfluorometric method. The inhibition of histamine release by the presenceof a test compound during challenge of the sensitized cells is a measureof the activity of the test compound. Dose response curves are preparedemploying various concentrations of the test substance and theconcentration which inhibits histamine release by 50% (IC₅₀) isdetermined by interpolation. Cromolyn sodium was found to exhibit anIC₅₀ of 1 μm in this test system. The compounds of the present inventionprepared by Procedures 2, 3, and 36 were substantially more potent thancromolyn sodium in that IC₅₀ values within the range of 0.3 to 0.8 μMwere exhibited.

Thus, there is provided by the present invention a method forsuppressing the allergic manifestations of immediate hypersensitivity insensitive warm blooded animals on exposure thereof to the causativeallergen. Mammals subject to immediate hypersensitivity sensitizationinclude man, mouse, rat, hamster, gerbil, dog, cat, sheep, goat, horse,cow, etc. The process involves administering an effective dose of one ofthe compounds of the present invention by the oral, topical, parenteral,or inhalational routes. The effective dosage range in rats is from about1 to 200 mg./kg. of body weight with the preferred compounds beingeffective orally in the range of from about 1 to 15 mg./kg. of bodyweight. The estimated human dose for the substance of Procedure 29 is inthe range of from 1 to 500 mg. orally.

Appropriate dosage unit forms for the foregoing application of thesubstances of Formulas I, IV, and V such as tablets, solutions orsuspensions for injection or inhalation, and powders for inhalation maybe prepared with conventional pharmaceutical carriers according toestablished practices in the pharmaceutical art.

The compounds of the present invention are prepared from the2-aminothiophene-3-carboxamides or 2-aminothiophene-3-carboxylic acidsof Formula II shown in the following diagram wherein Z is --OH or --NH₂.Compounds of Formula II have been previously described by Gewald, etal., Chem. Berichte 98, 3571 (1965), and ibid., 99, 94 (1966). Novelcompounds of Formula II for use in preparing compounds of this inventionmay be prepared by obvious adaptations of the Gewald, et al. methods. InFormula II the symbols L and B are independently selected from the groupconsisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, loweralkenyl having 3 to 6 carbon atoms, phenyl, alkanoyl having 2 to 6carbon atoms, or together they constitute cycloalkene having 5 to 7annular ring carbon atoms or R-substituted cycloalkene having 5 to 7annular ring carbon atoms wherein R is a lower alkyl group having 1 to 8carbon atoms. ##STR3##

The intermediate 2-aminothiophene-3-carboxamides or2-aminothiophene-3-carboxylic acids of Formula II on reaction with anacylating agent of Formula III yield the thiophene derivatives ofFormula IV or the oxazine derivatives of Formula V. R³ in Formulas IV,V, and VI is H, lower alkyl having 1 to 8 carbon atoms, or M wherein Mis a nontoxic pharmacologically acceptable metal cation. The acylatingagent of Formula III is an oxalic or 1,4-but-2-enedioic acid derivative.That is, A in the above formulas is either a covalent bond directlylinking the indicated groups or it is the vinyl group (--CH═CH--). X ischloro, bromo, or lower alkoxy having 1 to 8 carbon atoms and ispreferably the ethoxy group when operating on a starting material ofFormula II wherein Z is --OH, and chloro when operating on a startingmaterial of Formula II wherein Z is --NH₂.

For preparation of those substances of Formulas V and VI wherein A isthe vinyl group, it is preferred to employ the starting material ofFormula II wherein Z is --OH, and employ a lower alkyl diester or alower alkyl monoester halide of 1,4-but-2-enedioic acid as the acylatingagent.

For preparation of the intermediates of Formula IV wherein R³ is loweralkyl, the 2-aminothiophene-3-carboxamide of Formula II wherein Z is--NH₂ is treated in pyridine or other aprotic solvent such asacetonitrile, benzene, or di-isopropyl ether containing at least 1molecular proportion of pyridine relative to the acylating reactant ofFormula III which is preferably ethyl oxalyl chloride. The acylatingagent is carefully mixed with the solution of the carboxamide startingmaterial at room temperature using gradual addition of the acylatingagent to the intermediate or the reverse with cooling of the reactionvessel. It is undesirable to precool the reactants before commencementof the reaction. After the reaction subsides, a period of stirring atroom temperature is usually employed as a precaution to allow completionof the reaction. The intermediate of Formula IV is then recovered fromthe reaction mixture by pouring it into a protic solvent such asisopropanol and collecting the precipitated intermediate by filtration.

The thienyl intermediates of Formula IV are novel compounds havinganti-allergic activity, and are considered part of the presentinvention. The thienyl compounds of Formula IV wherein R³ is lower alkylare converted to the thienopyrimidines of the present invention havingFormula VI by heating in the molten state at a temperature in the rangeof about 200°-265° C., preferably the latter. The progress of thereaction can be estimated by the foaming which occurs due tovaporization of the water formed in the process as a by-product. In eachspecific instance the optimum temperature for carrying out the pyrolysiscan be estimated by visualization of the molten material when heated ina test tube and determining the temperature at which vigorous evolutionof water vapor occurs.

The oxazines of Formula V are novel compounds having antiallergicactivity and are considered part of the present invention. The oxazinesof Formula V wherein R³ is lower alkyl are prepared by reaction of a2-aminothiophene-3-carboxylic acid of Formula II wherein Z is --OH withan acylating agent of Formula III under much the same conditions asthose described above for the preparation of the intermediates ofFormula IV. In this instance it is preferred to employ two molecularportions of the acylating agent. If a single molecular portion ofacylating agent is employed, a mixture containing the intermediate2-carbamylthiophene-3-carboxylic acid analogous in structure to thethiophene carboxamides of Formula IV may be obtained. The2-carbamylthiophene-3-carboxylic acid may be cyclized to the oxazine ofFormula V by treatment with an additional molecular proportion of theacylating agent of Formula III or other cyclodehydrating agent such asSOCl₂. While stepwise operation in this fashion is possible, there is noadvantage. It is preferable to employ two molecular portions of FormulaIII acylating agent in the first instance, and to obtain the pureoxazine as the reaction product.

The oxazines of Formula V are converted to the thienopyrimidines ofFormula VI by reaction with an amine of the formula RNH₂ wherein R is asdefined above or an ammonium salt which is soluble in the reactionmedium. A protic solvent, and preferably a lower alkanol such as ethanolor isopropanol, is employed as reaction medium. The reaction is carriedout at the reflux temperature and the product usually crystallizes fromthe reaction mixture on cooling. Suitable ammonium salts are: ammoniumbenzenesulfonate, ammonium fluoride, ammonium fluorosulfonate, ammoniumfluosilicate, ammonium acetate, ammonium iodide, ammonium nitrate,ammonium hypophosphite, and ammonium valerate. It is preferred to employammonium acetate optionally in the presence of approximately onechemical equivalent of acetic acid to form a buffer system and minimizeamide formation from the 2-carboxy ester group.

The compounds of Formula I and VI wherein R³ is H or M are prepared byhydrolysis and neutralization of the corresponding esters (R³ is loweralkyl) as is exmplified in Procedures 3 and 32. The compounds of FormulaIV in which R³ is H or M are sometimes obtained as by-products in thepreparation of the Formula VI compounds from the Formula II compounds.They may also be prepared by hydrolysis and neutralization of a FormulaIV compound in which R³ is lower alkyl. The compounds of Formula Vwherein R³ is H may be prepared by selective hydrolysis of thecorresponding acid halide, and the M salts then formed byneutralization.

The compounds of Formula VI constitute a subgroup of the compounds ofFormula I wherein R² is CO₂ R³ or CH═CHCO₂ R³, and R⁵ and R⁶ of FormulaI correspond in part respectively to L and B of Formula VI. They serveas intermediates for other compounds of Formula I wherein R⁵ and R⁶ arehydroxy, alkoxy, nitro, amino, or halogen, or wherein R² is ##STR4##5-tetrazolyl, N-(tetrazol-5-yl)carbamyl, or CHO. Conventional aromaticsubstitution reactions known to be operable on substituted thiophenesmay be employed on Formula VI compounds wherein one of L and B ishydrogen to introduce the R⁵ or R⁶ group. For example, a compound ofFormula I wherein R⁵ or R⁶ is the nitro group is prepared by nitrationof the corresponding compound wherein R⁵ or R⁶, respectively, is ahydrogen atom, by treatment of a solution thereof in trichloroaceticacid and acetic anhydride with a solution of nitric acid intrichloroacetic acid. The reaction is carried out by a careful additionof the nitrating solution to the reactant solution at a temperature ofabout -15° C. Any temperature from about 0° to -20° C. may be employedwhich is convenient. The nitrothiophene is recovered from the reactionmixture by quenching with water and filtering the resulting precipitate.The resulting compound of Formula I wherein one of R⁵ and R⁶ is a nitrogroup may then be converted to the corresponding amino compound byconventional hydrogenation processes such as atmospheric pressurehydrogenation over a carbon-supported palladium catalyst employing asolvent medium for contact of the hydrogen with the catalyst andreactant.

The compounds of Formula I wherein one of R⁵ and R⁶ is the amino groupmay be converted by diazotization and replacement of the diazonium groupwith a halogen atom or a hydroxyl group according to known reactionconditions. For instance, the amino compound may be dissolved in aqueousfluoboric acid and treated with sodium nitrite at ice temperature toyield the corresponding diazonium fluoborate salt. The latter ontreatment with cuprous chloride, bromide, or iodide yields thecorresponding compound of Formula I wherein R⁵ or R⁶ is chloro, bromo,or iodo. The diazonium fluoroborate salts may also be converted to thecorresponding fluoro derivatives where one of R⁵ and R⁶ is the fluorogroup by heating at a temperature just above the melting point (standardScheimann reaction conditions). The iodo compounds may also be preparedby mercuration of a compound of Formula VI wherein L or B is hydrogen byreaction with mercuric acetate and treatment of the mercury derivativewith iodine and potassium iodide.

The compounds of Formula I wherein one of R⁵ and R⁶ is hydroxy areprepared from the intermediate diazonium fluoborate salts by hydrolysisthereof, preferably with potassium trichloroacetate in trichloroaceticacid followed by treatment of the reaction product with water. Thehydroxy compounds are converted to alkoxy compounds under conventionalalkylation conditions such as reaction with a diazoalkane, alkyl iodide,or dialkyl sulfate.

The compounds of Formula I in which R² is the hydroxymethyl group or anester thereof are prepared from the compounds of Formula I wherein R² isCO₂ R by reduction with a borohydride derivative such as lithiumborohydride or sodium borohydride. Again, conventional conditionsinvolving contacting the reactants in a reaction inert solvent mediumare employed. The compounds of Formula I wherein R² is thecarboxaldehyde group are prepared from the corresponding hydroxymethylcompounds by oxidation, for instance, with manganese dioxide ordimethylsulfoxide in dicyclohexylcarbondiimide under known conditions.

To sum up, the compounds of Formula I are prepared by means of a processwhich comprises reacting a compound of Formula II with an acylatingagent of Formula III to provide a compound of Formula IV or Formula V.The compound of Formula IV is then converted into a compound of FormulaI by heating in the molten state at a temperature in the range of200°-265° C. for from 5 to 15 min. The compound of Formula V isconverted into a compound of Formula I by treatment in solution with anamine of the formula R³ NH₂ or a soluble ammonium salt employing aprotic solvent such as a lower alkanol having 1 to 4 carbon atoms asreaction medium at the reflux temperature. The compound of Formula Ithus produced corresponds to the subgroup defined by Formula VI above.

If desired, a compound of Formula VI in which one of L or B is hydrogen,may be converted to the corresponding nitro compound by nitration underconditions which are known to be operable for the preparation of nitrosubstituted thiophene compounds by direct nitration of the correspondingunsubstituted thiophene compound. The resulting compound of Formula I inwhich R⁵ or R⁶ is nitro is then converted by catalytic hydrogenation ofthe nitro group to yield a compound of Formula I in which R⁵ or R⁶ isamino. The latter may then be diazotized to form the correspondingdiazonium salt, such as the fluoborate salt, which in turn may bereacted with a cuprous halide to provide a compound of Formula I whereinR⁵ or R⁶ is Cl, Br, or I or the diazonium salt may be hydrolyzed toyield the compound of Formula I wherein one of R⁵ or R⁶ is hydroxyl. Thediazonium fluoborate salt may also be heated to its decomposition pointto yield the compound of Formula I wherein one of R⁵ or R⁶ is fluoro.The hydroxy derivative may be etherified under conventional conditionsfor the formation of aromatic ethers to yield the compound of Formula Iwherein R⁵ or R⁶ is a lower alkoxy group having 1 to 6 carbon atoms.Further, a compound of Formula I in which R⁵ or R⁶ is hydrogen may beconverted by known methods to the mercuric acetate derivative and thenceto the corresponding compound where R⁵ or R⁶ is iodo by treatmemt of themercuric acetate derivative with I₂ and KI. This is illustrated in thefollowing flow sheet. ##STR5## Any of the foregoing compounds of FormulaVI in which A is a covalent bond linking the CO₂ R group to the ring maybe transformed into a compound of Formula I in which R² is 5-tetrazolylor N-(tetrazol-5-yl)-carbamoyl according to the following reactionscheme in which R, R⁵ and R⁶ have the same meaning as previously.##STR6##

DESCRIPTION OF SPECIFIC EMBODIMENTS

The nuclear magnetic resonance spectral characteristics reported in thefollowing procedures refer to the chemical shifts (δ) expressed as partsper million (ppm) versus tetramethylsilane as reference standard exceptin those instances where D₂ O is indicated as solvent where the HDO lineat 4.70 ppm was employed. The relative area reported for the variousshifts corresponds to the number of hydrogen atoms in the involvedsubstituent, and the nature of the shift as to multiplicity is reportedas broad singlet (bs), singlet (s), multiplet (m), doublet (d), triplet(t), or quadruplet (q) with coupling constant (J value) reported whereappropriate. The format is NMR (solvent): δ(multiplicity, relative area,J value). Abbreviations for the solvents are CDCl₃ (deuterochloroform),DMSO-d₆ (deuterodimethylsulfoxide), CF₃ CO₂ H (trifluoroacetic acid),and D₂ O (deuterium oxide). The infrared spectral data is a listing ofthe wavelengths in cm.⁻¹ of absorption maxima which are characteristicof functional groups. The infrared spectra were determined on potassiumbromide pellets containing 0.5% of the experimental substance.

Procedure 1. ETHYLN-[3-(AMINOCARBONYL)-4,5,6,7-TETRAHYDROBENZO[b]THIEN-2-YL]OXAMATE

A suspension of 72.92 grams (0.41 mole) of2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide in 200 ml. ofdry pyridine is stirred at 25° C. during the addition of 55.25 grams(0.41 mole) of ethyl oxalyl chloride dissolved in 50 ml. of dryacetonitrile in drop-wise fashion. Cooling of the reaction vessel byimmersion in ice water is employed and the flask is kept in the ice bathfor 30 min. after the addition is complete. The reaction vessel shouldnot be pre-cooled before commencement of the addition of the ethyloxalyl chloride. After the reaction is complete and the ice bath isremoved, 150 ml. of the acetonitrile is added to the reaction mixture tofacilitate stirring, and the mixture is kept overnight with stirring. Itis then poured into isopropanol and the precipitated product iscollected on a filter. The product is air dried, yielding 58.80 g. (49%)of a yellow solid, m.p. 204.0°-205.0° C. A sample of this materialrecrystallized from isopropanol exhibited the same melting point.

NMR (DMSO-d₆): 12.88 (s,1), 7.30 (s,2), 4.37 (q,2), 2.70 (m,4), 1.75(m.4), 1.37 (t,3). Infrared (KBr): 1635, 1680, and 1720 cm.⁻¹.

Anal. found: C, 52.68; H, 5.34; N, 9.42.

Procedure 2. ETHYL3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The product of Procedure 1, 8.89 g. (0.030 mole) is melted in a roundbottom flask equipped with a magnetic stirring bar and immersed in anoil bath at 261° C. The molten material is heated with stirring untilthe evolution of water as is evidenced by bubbling of the reactionmixture is no longer evident. About 5-15 min. is sufficient. The moltenmass is then dissolved in dimethylformamide and the warm solution ispoured into a volume of methanol larger than the reaction mixture. Theprecipitate is collected, and recrystallized from a mixture ofdimethylformamide and methanol to yield 4.92 g. (48%) of the desiredproduct as fine yellow needles, m.p. 207.0°-209.0° C.

NMR (CDCl₃): 10.35 (bs,1), 4.50 (q,2, J=7.0 Hz), 2.90 (m,4), 1.88 (m,4),1.47 (t,3). Infrared (KBr): 3110, 3030, 2940, 1740, 1670, 1570, 1490,1465, 1370, 1365, 1300, 1187, and 1035 cm.⁻¹. Ultraviolet absorptionmaxima (0.1 N-HCl) 255, 348 mμ; (0.1 N-NaOH) 275, and 311 mμ.

Anal. found: C, 55.92; H, 5.53; N, 10.04.

Procedure 3.3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]-PYRIMIDINE-2-CARBOXYLICACID DISODIUM SALT DIHYDRATE C₁₁ H₁₀ N₂ O₃ S.2Na.2H₂ O

The product of Procedure 2, 12.0 g. (0.043 mole) and 4.0 g. (0.10 mole)of sodium hydroxide is dissolved in a mixture of 440 ml. of water and160 ml. of ethanol and heated on a steam bath until dissolved. Followingdissolution of the starting material, there is a transient precipitationof the monosodium salt of the product. This material redissolves asheating is continued until a clear solution finally results. Thesolution is stirred at room temperature for 6 hrs. while the desireddisodium salt precipitates. The product is collected on a filter andair-dried, yield 10.4 g. (73%). This product failed to melt on heatingin a capillary tube at 355° C.

NMR (DMSO-d₆): 2.81 (m,4), 1.78 (m,4). Infrared (KBr): 2940, 1630, 1580,1550, 1490, 1435, 1390, 1350, 1320, 1275, 1050, 810, and 768 cm.⁻¹.

Anal. found: C, 40.27; H, 3.63; N, 8.40.

Procedure 4. ETHYL5-METHYL-6-OCTYL-4-OXO-4H-THIENO[2,3-d][1,3]OXAZINE-2-CARBOXYLATE

To a suspension of 2-amino-4-methyl-5-(n-octyl)thiophene-3-carboxylicacid hydrate (1/4H₂ O), 6.88 g. (0.025 mole), in 25 ml. of dry pyridinewhich is first cooled to 0° C. there is added 6.92 g. (0.051 mole) ofethyl oxalyl chloride in drop-wise fashion. The mixture is stirred at25° C. for 1 hr. after the addition is complete and then poured into 1l. of cold water. The product precipitates and is recovered byextraction with octane; yield 6.4 g. (73%), recrystallized from lowboilig petroleum ether, white crystals, m.p. 66.0°-69.0° C.

NMR (CDCl₃): 4.48 (q.2, J=7.1 Hz), 2.81 (t,2, J=6.8 Hz), 2.45 (s,3),1.44 (t,3, J=7.1 Hz), 1.28 (m,12), and 0.88 (m,3). Infrared (KBr): 2960,2930, 2860, 1765, 1742, 1588, 1468, 1448, 1368, 1310, 1198, 1150, 1100,1020, and 770 cm.⁻¹.

Anal. found: C, 61.48; H, 7.21; N, 3.89.

Procedure 4 may be modified by employing2-[[(ethoxycarbonyl)carbonyl]amino]-4-methyl-5-octylthiophene-3-carboxylicacid as starting material and employing one equivalent of ethyl oxalylchloride to effect the cyclization.

Procedure 5. ETHYL3,4-DIHYDRO-5-METHYL-6-OCTYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

A mixture of 5.54 g. (0.016 mole) of the product of Procedure 4, 1.10 g.(0.0143 mole) of ammonium acetate, and 0.385 g. (0.0064 mole) of aceticacid in 50 ml. of absolute ethanol is heated on a steam bath for 40 min.Upon cooling, the desired product crystallizes in the form of needleswhich are collected on a filter and dried, yield 4.39 g. (79%). Afterrecrystallization from isopropanol, the material was obtained asoff-white needles, m.p. 136.0°-137.0° C.

NMR (CDCl₃): 4.51(q.2, J=7.1 Hz), 2.80(t,2, J=6.8 Hz), 2.53(s,3),1.46(t,3, J=7.1 Hz), 1.30(m,12), 0.89(m,3).

Infrared (KBr): 3180, 3100, 3040, 2925, 2850, 1740, 1680, 1570, 1492,1470, 1370, 1305, 1193, and 1033 cm.⁻¹.

Anal. found: C, 61.53; H, 7.37; N, 8.01.

Procedures 6-12. Additional Thienyloxamates. By adaptation of the methodof Procedure 1 to the appropriately substituted2-aminothiophene-3-carboxamides, the following correspondinglysubstituted ethyl N-[3-(aminocarbonyl)thien-2-yl]oxamates are prepared.The physical properties and recrystallization solvents are notedfollowing the name of each of these substances in Table I.

                                      TABLE I                                     __________________________________________________________________________    Thienyloxamates                                                               Procedure No.                                                                         Name                                                                  __________________________________________________________________________    6       ETHYL [3-(AMINOCARBONYL)-5-PHENYLTHIEN-2-YL]OXAMATE.                          Recrystallized from ethanol-isopropanol, m.p. 198°-                    200° C.                                                                Anal. found: C, 56.70; H, 4.56; N, 8.87                               7       ETHYL N-[3-(AMINOCARBONYL)-4-METHYL-5-PHENYLTHIEN-2-YL]-                      OXAMATE.- Recrystallized from dimethylformamide-                              ethanol, m.p. 175°-176° C.                              8       ETHYL N-[3-(AMINOCARBONYL)-5-HEXYL-4-METHYLTHIEN-2-YL]-                       OXAMATE.- Recrystallized from isopropyl acetate-                              isopropyl ether, m.p. 147°-149° C.                              Anal. found: C, 56.31; H, 7.24; N, 8.25                                       Hydrolysis of this substance yields N-[3-Aminocarbonyl)-                      5-hexyl-4-methylthien-2-yl]oxamic acid sodium salt,                           C.sub.14 H.sub.20,N.sub.2 O.sub.4 S . Na salt, m.p. > 350°             C.                                                                    9       ETHYL N-[3-(AMINOCARBONYL)-4-METHYLTHIEN-2-YL]OXAMATE.-                       Recrystallized from dimethylformamide-absolute                                ethanol, m.p. 196°-198° C.                                      Anal. found: C, 46.86; H, 4.78; N, 10.76.                             10      ETHYL N-[3-(AMINOCARBONYL)-4-METHYL-5-PENTYLTHIEN-2-                          YL]OXAMATE.- Recrystallized from isopropanol, m.p. 153°-               154° C.                                                        11      ETHYL N-[3-(AMINOCARBONYL)-4-METHYL-5-(3-METHYL-2-                            BUTENYL)-2-YL]OXAMATE. -Recrystallized from iso-                              propanol, m.p. 199°-200° C.                             12      ETHYL N[3-(AMINOCARBONYL)-6-tert-BUTYL-4,5,6,7-TETRA-                         HYDROBENZO[b]THIEN-2-YL]OXAMATE.- Recrystallized from                         chloroform-ethanol, m.p. 228.5°-231.5° C.                       Anal. found: C, 58.28; H, 7.03; N, 7.80                               __________________________________________________________________________

Procedures 13-19. Additional Thienopyrimidine-2-Carboxylates byCyclization of Thienyloxamates

The products of the present invention, which are listed in Table II,were prepared by heating the molten thienyloxamates listed in Table Iaccording to the method of Procedure 2 above. In Table II the figure inparenthesis following the Procedure No. is the procedure number for thepreparation of the starting material employed.

                                      TABLE II                                    __________________________________________________________________________    Thienopyrimidine-2-Carboxlates                                                Procedure No.                                                                         Name                                                                  __________________________________________________________________________    13 (6)  ETHYL 3,4-DIHYDRO-4-OXO-6-PHENYLTHIENO[2,3-d]PYRIMIDINE-                      2-CARBOXYLATE.-Recrystallized from acetonitrile, yellow                       crystalline solid, m.p. 228.0°- 232.0° C.                       NMR (CDCl.sub.3): 10.80 (bs,1), 7.71 (s,l), 7.45 (m,5), 4.52                  (q,2, J = 7.0 Hz), and 1.48 (t,3, J =7.0 Hz,).                                Infrared (KBr): 3440, 3090, 3050, 1720, 1667, 1560, 1468,                     1440, 1365, 1178, 1030, 840, 750, and 684 cm..sup.-1.                         Anal. found: C, 59.87; H, 4.03; N, 9.32.                              14 (7)  ETHEL 3,4-DIHYDRO-5-METHYL-4-OXO-6-PHENTYLTHIENO[2,3-d]-                      PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from dimethyl-                      formamide-ethanol, m.p. 225.5°-227.5° C., yellow                crystal-                                                                      line solid.                                                                   NMR (CDCl.sub.3): 10.40 (bs,1), 7.39 (m,5), 4.51 (q,2, J =                    7.1 Hz), 2.65 (s,3), 1.47 (t.3, J = 7.1 Hz).                                  Infrared (KBr): 3160, 3090, 3020, 2980, 2930, 1727, 1665,                     1565, 1480, 1368, 1300, 1175, 1030, 1005, 778, 760, 737                       and 695 cm..sup. -1.                                                          Anal. found: C, 61.02; H, 4.38; N, 8.87.                              15 (8)  ETHYL 3,4-DIHYDRO-6-HEXYL-5-METHYL-4-OXOTHIENO[2,3-d]-                        PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from isopro-                        panol, yellow needles, m.p. 134.0°-135.0°  C.                   NMR (CDCl.sub.3): 10.33 (bs,1), 4.49 (q.2, J= 7.1 Hz),                        2.79 (t,2, J = 7.0 Hz), 2.50 (s,3), 1.43 (t,3, J =                            7.1 Hz), 1.36 (m,8), 0.88 (m,3).                                              Infrared (KBr): 3100, 2020, 2840, 1734, 1672, 1565,                           1488, 1460, 1365, 1300, 1185, and 1030 cm..sup.-1.                            Anal. found: C, 59.90; H, 6.92; N, 8.61.                              16 (9)  ETHYL 3,4-DIHYDRO-5-METHYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-                      2-CARBOXYLATE.- Recrystallized from ethanol, pale                             yellow crystals, m.p. 151.5°-162.0° C.                          NMR (DMS0-d.sub.6): 12.50 (bs,1), 7.33 (q,1, J = 1.1 Hz),                     4.37 (q,2, J = 7.1 Hz), 2.50 (d,3, J = 1.1 Hz,) and                           1.35 (t,3, J = 7.1 Hz).                                                       Infrared (KBr): 3180, 3080, 1732, 1672, 1570, 1490,                           1370, 1300, 1285, 1180, 1155, 1035, and 1010 cm..sup.-1.                      Anal. found: C, 50.24; H, 4.22; N, 11.72.                             17 (10) ETHYL 3,4-DIHYDRO-5-METHYL-4-OXO-6-PENTYLTHIENO[2,3-d]-                       PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from isopro-                        panol, olive-green crystals, m.p. 152.5°-153.5° C.              NMR (CDCl.sub.3): 9.80 (bs,1), 4.52 (q,2, J = 7.2 Hz), 2.81                   (t,2, J = 6.5 Hz), 2.52 (s,3), 1.46 (t,3, J =  7.2 Hz)                        1.38 (m,6), and 0.91 (m,3).                                                   Infrared (KBr): 3080, 3020, 2950, 2920, 2842, 1738,                           1675, 1568, 1490, 1365, 1300, 1090, and 1030 cm..sup.-1.                      Anal. found: C, 58.42; H, 6.65; N, 9.19.                              18 (11) ETHYL 3,4-DIHYDRO-5-METHYL-6-(3-METHYL-2-BUTENYL)-4-                          OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE.- Chromato-                          graphed on silica gel and eluted with chloroform.                             Evaporation of solvent yielded an oil with failed to                          crystallize. The nuclear magnetic resonance spectrum                          indicated that the product was a mixture of the above                         named compound and the -6-(3-methyl-1-butenyl)isomer.                 19 (12) ETHYL 7-t-BUTYL-3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO-                       [2,3-d]PYRIMIDINE-2-CARBOXYLATE.- Chromatographed on                          silica gel (hexane) and eluted with ether. Recrystal-                         lized from isopropanol, pale yellow powder, m.p. 180.0°-               183.0° C.                                                              NMR (CDCl.sub.3): 10.30 (bs,1), 4.50 (q,2, J = 7.1 Hz), and                   0.95 (s,9).                                                                   Infrared (KBr): 2930, 1730, 1662, 1362, 1300, 1281,                           1180, and 1092 cm..sup.-1.                                                    Anal. found: C, 61.30; H, 6.60; N, 8.35.                              __________________________________________________________________________

Procedures 20-26. Thienooxazine-2-carboxylic Acids

The following thienooxazines are prepared by substitution of theappropriately substituted 2-aminothiophene-3-carboxylic acids in themethod of Procedure 4. The thienooxazines are listed in Table III withtheir physical properties and procedural modifications where such arerequired.

                                      TABLE III                                   __________________________________________________________________________    Thienooxazine-2-Carboxylic Acids                                              Procedure No.                                                                         Name                                                                  __________________________________________________________________________    20      ETHYL 5,6,7,8-TETRAHYDRO-4-OXO-4H-BENZOTHIENO[2,3-d]-                         [1,3]OXAZINE-2-CARBOXYLATE. Recrystallized from                               isopropyl acetate as the hydrate (1/4 H.sub.2 O), yellow                      solid, m.p. 148.5°-180.5° C.                                    NMR (DMSO-d.sub.6): 4.32 (q,2, J = 7.1 Hz), 2.79 (m,4),                       1.79 (m,4) and 1.33 (t,3, J = 7.1 Hz).                                        Infrared (KBr): 2990, 2950, 2880, 1767, 1740, 1640,                           1582, 1560, 1460, 1372, 1350, 1300, 1185, 1150, 1090,                         1020, and 768 cm..sup.-1.                                                     Anal. found: C, 55.23; H, 5.06; N, 4.96.                              21      ETHYL 6-ETHYL-5-METHYL-4-OXO-4H-THIENO[2,3-d][1,3]-                           OXAZINE-2-CARBOXYLATE.- 1:1 pyridine-acetonitrile                             was used as reaction medium; chromatographed on silica                        gel (CHCl.sub.3): recrystallized from isopropyl ether,                        light yellow needles, m.p. 97.5°-99.5° C.                       NMR (DMSO-d.sub.6): 4.36 (q,2, J = 7.1 Hz), 2.88 (q,2, J =                    7.1 Hz), 2.38 (s,3), 1.32 (t,3, J = 7.1 Hz), and 1.22                         (t,3, J = 7.2 Hz). -  Infrared (KBr): 2980, 1778, 1760, 1590,                 1544, 1470,                                                                   1450, 1390, 1320, 1275, 1210, 1170, 1110, 1025, 954,                          924, 915, and 771 cm..sup.-1.                                                 Anal. found: C, 54.27; H, 4.94; N, 5.13.                              22      ETHYL 5-METHYL-6-(2-METHYLPROPYL)-4-OXO-4H-THIENO[2,3-d]-                     [1,3]OXAZINE-2-CARBOXYLATE.- Recrystallized hexane,                           m.p. 78.5°-79.5° C.                                             NMR (DMSO-d.sub.6): 4.35 (q,2, J = 7.0 Hz), 2.72 (d,2, J =                    6.8 Hz), 2.38 (s,3), 1.87 (m,1), 1.32 (t,3, J = 7.0 Hz),                      and 0.92 (d,6, J = 6.5 Hz).                                                   Infrared (KBr): 2960, 2935, 2880, 1764, 1740, 1592,                           1470, 1374, 1320, 1196, 1160, 1102, and 770 cm..sup.-1.                       Anal. found: C, 57.31; H, 5.77; N, 4.84.                              23      ETHYL 6-ETHYL-4-OXO-4H-THIENO[2,3-d][1,3]OXAZINE-2-                           CARBOXYLATE.- 13:1 acetonitrile-pyridine was used as                          reaction medium; recrystallized from ethyl acetate-                           low boiling petroleum ether, light yellow needles,                            m.p. 109.0°-111.0° C.                                           NMR (CDCl.sub.3): 7.18 (m,1), 4.48 (q,2, J = 7.1 Hz),                         2.92 (m,2), 1.43 (t,3, J = 7.1 Hz), and 1.36 (t,3, J =                        7.2 Hz).                                                                      Infrared (KBr): 3110, 3000, 1982, 1773, 1752, 1590,                           1540, 1375, 1331, 1314, 1215, 1172, 1090, 844, and 769                        cm..sup.-1.                                                                   Anal. found: C, 51.93; H, 4.26; N, 5.55.                              24      ETHYL 6-ACETYL-5-METHYL-4-OXO-4H-THIENO[2,3-d][1,3]-                          OXAZINE-2-CARBOXYLATE.- 3:8 pyridine-acetonitrile was                         used as reaction medium; chromatographed on silica gel                        (CHCl.sub.3), recrystallized chloroform-hexane, pale yellow                   platelets, m.p. 102.0°-103.0° C.                                NMR (CDCl.sub.3): 4.50 (q,2, J = 7.1 Hz), 2.89 (s,3), 2.62                    (s,3), 1.46 (t,3, J = 7.1 Hz).                                                Infrared (KBr): 2992, 1770, 1752, 1671, 1594, 1510, 1312,                     1274, 1238, 1188, 1131, 929, 770, and 574 cm. .sup.-1.                        Anal. found: C, 51.03; H, 3.92, N, 4.86.                              25      ETHYL 3,4-DIHYDRO-5,6-DIMETHYL-4-OXOTHIENO[2,3-d][1,3]-                       OXAZINE-2-CARBOXYLATE.- 2:1 pyridine-acetonitrile was                         used as reaction medium; recrystallized ethanol, dark                         brown crystals, m.p. 129°-130° C.                               NMR (CDCl.sub.3): 4.409 (q, 2, J = 7.2 Hz), 2.44 (s,6),                       1.44 (t,3, J = 7.2 Hz).                                                       Infrared (KBr): 3002, 2980, 1774, 1748, 1590, 1554,                           1460, 1372, 1322, 1294, 1208, 1170, 1110, 1030, 958,                          872, and 775 cm.sup.-1.                                                       Anal. found: C, 51.95; H, 4.49; N, 5.30.                              26      ETHYL 6-HEXYL-5-METHYL-4-OXO-4H-THIENO[2,3-d][1,3]-                           OXAZINE-2-CARBOXYLATE.- 5:1 acetonitrile-pyridine was                         used as reaction medium; recrystallized from low boiling                      petroleum ether-ethyl ether, light tan solid, m.p.                            56.5°-57.0° C.                                                  NMR (CDCl.sub.3): 4.63 (q,2, J = 7.0 Hz), 2.92 (t,2, J =                      6.8 Hz), 2.47 (s,3), 1.46 (t,3, J = 7.0 Hz), 1.36 (m,8),                      and 0.90 (m,3).                                                               Infrared (KBr): 2950, 2920, 2850, 1750, 1580, 1465, 1440,                     1370, 1318, 1278, 1205, 1160, 1096, 1016, 920, 906, and                       765 cm..sup.-1.                                                               Anal. found: C, 59.44; H, 6.42; N, 4.26; S, 10.01                     __________________________________________________________________________

Procedures 27-31. Additional Thienopyrimidine-2-carboxylates FromThieno-oxazine-2-carboxylates

The method of Procedure 5 is adapted to the preparation of the compoundslisted in Table IV by substitution of the appropriately substitutedthieno-oxazine-2-carboxylate as starting material. The products producedare identified in Table IV along with information as to purification andidentification. The number in parenthesis next to the Procedure No.identifies the procedure for preparation of the starting material. Thestarting materials are listed in Table III.

                                      TABLE IV                                    __________________________________________________________________________     Thienopyrimidine-2-Carboxylates                                              Procedure No.                                                                         Name                                                                  __________________________________________________________________________    27 (21) ETHYL 6-ETHYL-3,4-DIHYDRO-5-METHYL-4-OXOTHIENO[2,3-d]-                        PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from absolute                       ethanol, white flakes, m.p. 148.5°-173.5° C.                    NMR (CDCl.sub.3): 4.51 (q,2, J = 7.1 Hz), 2.85 (q,2 J = 7.3 Hz),              2.25 (s,3), 1.46 (t,3, J = 7.1 Hz), and 1.30 (t,3, J = 7.3 Hz).               Infrared (KBr): 3180, 3100, 2060, 2930, 1730, 1680, 1555,                     1488, 1460, 1368, 1300, 1186, and 1032 cm..sup.-1.                            Anal. found: C, 54.17; H, 5.50; N, 10.029.                            28 (22) ETHYL 3,4-DIHYDRO-5-METHYL-6-(2-METHYLPROPYL)-4-OXOTHIENO-                    [2,3-d]PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from                         isopropanol, off-white crystals, m.p. 175°-176° C.              NMR (DMSO-d.sub.6): 12.40 (bs,1), 4.36 (q,2, J = 7.1 Hz),                     2.68 (d,2, J = 6.7 Hz), 2.43 (s,3), 1.88 (m,1), 1.34                          (t,3, J = 7.1 Hz), and 0.92 (d,6, J = 6.5 Hz).                                Infrared (KBr): 3090, 2960, 2930, 2870, 1740, 1675,                           1570, 1490, 1467, 1383, 1369, 1305, 1194, 1034, and                           768 cm.sup.-1.                                                                Anal. found:                                                          29 (23) ETHYL 6-ETHYL-3,4-DIHYDRO-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-                     CARBOXYLATE.- Recrystallized from ethanol, pale yellow                        needles, m.p. 163.0°-168.0° C.                                  NMR (CDCl.sub.3): 10.30 (bs,1), 7.26 (t,1, J = 1.1 Hz), 4.55                  (q,2, J = 7.0 Hz), 2.92 (m,2), 1.48 (t,3, J = 7.0 Hz) and                     1.38 (t,3, J = 7.2 Hz).                                                       Infrared (KBr): 3180, 3120, 3045, 2980, 2945, 2890, 1749,                     1694, 1579, 1949, 1376, 1315, 1194, 1046, 852, 848, and                       770 cm.sup.-1.                                                                Anal. found: C, 52.48; H, 4.84; N, 11.21.                             30 (24) ETHYL 6-ACETYL-3,4-DIHYDRO-5-METHYL-4-OXOTHIENO[2,3-d]-                       PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from dimethyl-                      formamide-ethanol, off-white needles, m.p. 236.0°-242.0.deg            ree. C.                                                                       NMR (DMSO-d.sub.6): 12.30 (bs,1), 4.38 (q,2, J = 7.0 Hz),                     2.84 (s,3), 2.58 (s,3) and 1.35 (t,3, J = 7.0 Hz).                            Infrared (KBr): 3100, 2980, 1732, 1697, 1665, 1572, 1512,                     1430, 1368, 1310, 1233, 1185, and 1027 cm..sup.-1.                            Anal. found C, 51.17; H, 4.15; N, 9.90.                               31 (25) ETHYL 3,4-DIHYDRO-5,6-DIMETHYL-4-OXOTHIENO[2,3-d]-                            PYRIMIDINE-2-CARBOXYLATE.- Recrystallized from aceto-                         nitrile, brown crystalline solid, m.p. 211.5°-212.5°             C.                                                                           NMR (CDCl.sub.3): 10.60 (bs,1), 4.60 (q,2, J = 7.2 Hz),                       2.54 (s,3), 2.45 (s,3), and 1.47 (t,3, J = 7.2 Hz).                           Infrared (KBr): 3170, 3100, 2992, 2920, 1736, 1680,                           1562, 1490, 1362, 1298, 1188, 1162, 1035, 1019, and                           775 cm.sup.-1.                                                                Anal. found: C, 52.14; H, 4.62; N, 10.89                              __________________________________________________________________________

Procedure 32.3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLICACID MONOHYDRATE

The product of Procedure 3, 5.0 g. is dissolved in 150 ml. of warm waterand the solution clarified by filtration. The filtrate is acidified withglacial acetic acid and refrigerated overnight. The precipitate iscollected, washed on the filter with water and dried, cream coloredsolid, m.p. 254.5°-256.5° C.

NMR (DMSO-d₆): 2.84 (m,4), 1.79 (m,4).

Infrared (KBr): 3470, 3100, 3020, 2940, 1695, 1660, 1490, 1440, 1300,1197, 1145, 1033, 960, and 720 cm.⁻¹.

Anal. found: C, 49.39; H, 4.20; N, 10.33.

Procedures 33-45. Additional Thienopyrimidine-2-carboxylic Acid MetalSalts

The method of Procedure 3 is applied to various otherthienopyrimidine-2-carboxylic esters with the production of varioussalts. The substances produced are listed in Table V along withreference to the source of the starting material identified by procedurenumber shown in parenthesis adjacent to the Procedure No., and theanalytical information with respect to these products.

                                      TABLE V                                     __________________________________________________________________________    Salts                                                                         Procedure No.                                                                         Name                                                                  __________________________________________________________________________    33 (5)  3,4-DIHYDRO-5-METHYL-6-OCTYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-                    2-CARBOXYLIC ACID DISODIUM SALT HYDRATE C.sub.16 H.sub.22 N.sub.2             O.sub.3 S . 2Na . H.sub.2 O. -                                                Failed to melt at 300° C.                                              NMR (DMSO-d.sub.6): 2.79 (t,2 J = 6.9 Hz.), 2.45 (s,3),                       1.26 (m,12), and 0.86 (m,3).                                                  Infrared (KBr): 2980, 2945, 2876, 1660, 1630, 1580, 1553,                     1493, 1445, 1392, 1360, 1060, and 814 cm..sup.-1.                             Anal. found: C, 49.81; H, 5.75; N, 7.05.                              34 7.2 Hz), 3,4-DIHYDRO-4-OXO-6-PHENYLTHIENO[2,3-d]PYRIMIDINE-2-                      CARBOXYLIC ACID SODIUM SALT HEMIHYDRATE C.sub.13 H.sub.8 N.sub.2              O.sub.3 S . Na . 1/2H.sub.2 O.-                                               Crude disodium salt prepared as in Procedure 3 was                            dissolved in warm water and carefully acidified with                          acetic acid until a white precipitate formed; white                           powder, m.p. 292.0°-294.0° C. (dec.).                           NMR (DMSO-d.sub.6): 7.80 (s,2), 7.71 (m,2) and 7.38 (m,3).                    Infrared (KBr): 3430, 3230, 1660, 1465, 1440, 1360, 1290,                     1180, 1040, 810, 750, 700, and 685 cm..sup.-1.                                Anal. found: C, 51.61; H, 3.33; N, 9.08.                              35 (14) 3,4-DIHYDRO-5-METHYL-4-OXO-PHENYLTHIENO[2,3-d]-                               PYRIMIDINE-2-CARBOXYLIC ACID DISODIUM SALT HYDRATE                            C.sub.14 H.sub.10 N.sub.2 O.sub.3 S . 2Na . H.sub.2 O. - Failed               to melt at 350° C.                                                     NMR (CF.sub.3 COOH): 7.46 (s,5), 2.71 (s,3).                                  Infrared (KBr): 3450, 2970, 2930, 1620, 1570, 1490, 1440,                     1385, 1365, 1295, 1070, 1050, 810, 765, 750. and 700 cm..sup.-1.              Anal. found: C. 48.14; H, 2.83; N, 8.07.                              36 (15) 6-HEXYL-3,4-DIHYDRO-5-METHYL-4-OXOTHIENO[2,3-d]-                              PYRIMIDINE-2-CARBOXYLIC ACID DISODIUM SALT HYDRATE                            C.sub.14 H.sub.18 N.sub.203 S . 2Na . 1/4H.sub.2 O. - Isopropanol             added to induce preci-                                                        pitation; recrystallized from hot water; pale yellow solid,                   failed to melt at 360° C.                                              NMR (CF.sub.3 COOH): 3.02 (t,2, J = 6.5 Hz), 2.63 (s,3), 1.46                 (m,8), and 0.94 (m,3).                                                        Infrared (KBr): 2960, 2930, 2860, 1650, 1565, 1480,                           1379, 1045, and 785 cm..sup.-1.                                               Anal. found: C, 49.31; H, 5.30; N, 8.18.                              37 (16) 3,4-DIHYDRO-5-METHYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-                          CARBOXYLIC ACID DISODIUM SALT DIHYDRATE C.sub.8 H.sub.6 N.sub.2               O.sub.3 S . 2Na . 2H.sub.2 O.-                                                Product recovered by evaporation of solvent and tritura-                      tion of residue with hot methanol; off-white powder,                          failed to melt at 300° C.                                              NMR (D.sub.2 O): 6.84 (m,1), 2.49 (m,3).                                      Infrared (KBr): 2940, 1660. 1630, 1582, 1539, 1510, 1490,                     1439, 1390, 1380, 1350, 12980, 1076, 1055, 814, 801, 620                      cm..sup.-1.                                                                   Anal. found: C, 33.40; H, 2.13; N, 9.44.                              38 (17) 3,4-DIHYDRO-5-METHYL-4-OXO-6-PENTYLTHIENO[2,3-d]PYRIMIDINE-                   2-CARBOXYLIC ACID DISODIUM SALT SESQUIHYDRATE C.sub.13 H.sub.16               N.sub.2 O.sub.3 S . 2Na .                                                     11/2H.sub.2 O. Light yellow solid, failed to melt at 350°              C.                                                                            NMR: 3.00 (t,2, J = 6.5 Hz), 2.62 (s,3), 1.50 (m,6) and                       0.96 (m,3).                                                                   Infrared (KBr): 2960, 2924, 2878, 2860, 1654, 1620, 1571,                     1482, 1438, 1384, 1370, 1350, 1050, and 805 cm..sup.-1.                       Anal. found: C, 44.46; H, 4.85; N, 7.90.                              39 (18) 3,4-DIHYDRO-5-METHYL-6-(3-METHYL-2-BUTENYL)-4-OXOTHIENO-                      [2,3-d]PYRIMIDINE-2-CARBOXYLIC ACID DISODIUM SALT SESQUI-                     HYDRATE C.sub.13 H.sub.14 N.sub.2 O.sub.3 S . 2Na . 11/2H.sub.2               O. - Precipitated from reaction                                               after evaporation of alcohol by addition of isopropanol;                      yellow solid, failed to melt at 350° C.                                NMR (CF.sub.3 COOH): 6.70 (m,2), 5.55 (m,1), 3.72 (m,3), 2.71                 (s,6), 1.85 (m,6), and 1.22 (d,6, J = 6.5 Hz).                                Infrared (KBr): 3420, 2965, 2925, 1655, 1625, 1572, 1432,                     1384, 1370, 1350, 1050, and 805 cm..sup.-1.                                   Anal. found: C, 44.37; H, 3.94; N, 7.88.                              40 (19) 7-t-BUTYL-3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]-                      PYRIMIDINE-2-CARBOXYLIC ACID DISODIUM SALT DIHYDRATE,                         C.sub.15 H.sub.16 N.sub.2 O.sub.3 S . 2Na . 2H.sub.2 O. -                     Dimethylsulfoxide sulfoxide was added to                                      the reaction mixture for solubilization; product precipi-                     tated with isopropanol; failed to melt at 300° C.                      NMR (CF.sub.3 COOH): 2.98 (m,4), 2.18 (m,2), 1.67 (m,1), and                  1.02 (s,9). Infrared (KBr): 2960, 1650, 1600, 1572,                           1540, 1479, 1430, 1382, 1317, 1045, and 780 cm..sup.-1.                       Anal. found: C, 46.76; H, 4.92; N, 7.01.                              41 (25) 3,4-DIHYDRO-5,6-DIMETHYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-                        2-CARBOXYLIC ACID DISODIUM SALT SESQUIHYDRATE                                 C.sub.9 H.sub.8 N.sub.2 O.sub.3 S . 2Na . 11/2H.sub.2 O. -                    Product precipitated from aqueous                                             reaction mixture with isopropanol; gray solid, failed                         to melt at 350° C.                                                     NMR (CF.sub.3 COOH): 2.64 (s,6). Infrared (Kbr): 2920, 1650,                  1620, 1578, 1550, 1484, 1430, 1384, 1380, 1350, 1280,                         1200, 1050, and 807 cm..sup.-1.                                               Anal. found: C, 3665; H, 2.90; N, 9.36.                               42 (27) 6-ETHYL-3,4-DIHYDRO-5-METHYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-                    2-CARBOXYLIC ACID DISODIUM SALT DIHYDRATE C.sub.10 H.sub.10                   N.sub.2 O.sub.3 S . 2Na .                                                     2H.sub.2 O. - Isopropanol was added to the reaction mixture to                induce crystalization of the product; white solid, failed                     to melt at 360° C.                                                     NMR (D.sub.2 O): 2.95 (q,2, J = 7.2 Hz), 2.49 (s,3), 1.30 (t,3,               J = 7.2 Hz). Infrared (KBr): 2975, 2940, 1650, 1620, 1570,                    1540, 1484, 1435, 1386, 1355, 1320, 1278, 1050, 808 cm..sup.-1.               Anal. found: C, 37.73; H, 3.41; N, 8.46.                              43 (28) 3,4-DIHYDRO-5-METHYL-6-(2-METHYLPROPYL)-4-OXOTHIENO-                          [2,3-d]PYRIMIDINE-2-CARBOXYLIC ACID DISODUM SALT                              SESQUIHYDRATE C.sub.12 H.sub.14 N.sub.2 O.sub.3 S . 2Na .                     11/2H.sub.2 O. - Product preci-                                               pitated from the reaction mixture on addition of isopro-                      panol; white solid, failed to melt at 350° C.                          NMR (CF.sub.3 COOH): 2.89 (d,2, J = 7.0 Hz), 2.63 (s,3), 1.95                 (m,2), 1.41 (m,1), 1.05 (d,6 J = 6.5 Hz).                                     Infrared (KBr): 2950, 2922, 2865, 1650, 1620, 1565,                           1530, 1465, 1380, 1355, 1200, 1045, and 802 cm..sup.-1.                       Anal. found: C, 42.81; H, 4.62; N, 8.35.                              44 (29) 6-ETHYL-3,4-DIHYDRO-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-                           ARBOXYLIC ACID DISODIUM SALT DIHYDRATE C.sub.9 H.sub.8 N.sub.2                O.sub.3 S . 2Na . 2H.sub.2 O. -                                               Methanol was used as reaction solvent; white powder,                          failed to melt at 360° C.                                              NMR (D.sub.2 O): 6.89 (s,1), 2.68 (q,2, J = y7.2 Hz), 1.12 (6,3,              J = 7.2 Hz).                                                                  Infrared (KBr): 3440, 2980, 2942, 1660, 1580, 1540, 1498,                     1428, 1350, 1050, 854, 800, and 758 cm..sup.-1.                               Anal. found: C, 35,63; H, 3.07; N, 9.12.                              45 (30) 6-ACETYL-3,4-DIHYDRO-5-METHYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-                   2-CARBOXYLIC ACID DISODIUM SALT SESQUIHYDRATE C.sub.10 H.sub.8                N.sub.2 O.sub.4 S .                                                           2Na . 11/2H.sub.2 O. - Yellow solid which fails to melt at                    360° C.                                                                NMR (CF.sub.3 COOH): 3.10 (s,3), 2.83 (s,3).                                  Infrared (KBr): 3460, 1665, 1633, 1580, 1484, 1438,                           1370, 1350, 1305, 1259, 1060, and 812 cm..sup.-1.                             Anal. found: C, 37.20; H, 2.65; N, 8.36.                              46 (58) E-3-(3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]-                           PYRIMIDIN-2-YL)-2-PROPENOIC ACID DISODIUM SALT                                HYDRATE C.sub.13 H.sub.10 N.sub.2 O.sub.3 S . 2Na . 3 . 5H.sub.2              O. - Product precipitated                                                     by treatment of the reaction mixture with isopropanol;                        tan solid, failed to melt at 300° C.                                   NMR (DMSO-d.sub.6): 6.98 (s,2), 2.80 (m,4), 1.75 (m,4).                       Infrared (KBr): 3400, 2930, 2850, 1652, 1565, 1540, 1395,                     1290, 1150, 968, and 806 cm..sup.-1.                                          Anal. found: C, 40.50; H, 4.10; N, 7.12.                              47 (51) 5-AMINO-6-ETHYL-3,4-DIHYDRO-4-OXOTHIENO[2,3-d]PYRIMIDINE-                     2-CARBOXYLIC ACID DISODIUM SALT SESQUIHYDRATE                                 C.sub.9 H.sub.7 N.sub.3 O.sub.3 S . 2Na . 1 . 5H.sub.2 O. -                   Methanol used as reaction medium;                                             product precipitated with isopropanol; yellow powder,                         failed to melt at 250° C.                                              NMR (DMSO-d.sub.6): 2.84 (q,2, J = 7.2 Hz), 1.25 (t,3, J = 7.2                Hz).                                                                          Infrared (KBr): 3405, 2975, 1655, 1625, 1590, 1538,                           1505, 1410, 1360, 1295, 1050, 809, and 765 cm..sup.-1.                        Anal. found: C, 35.34; H, 3.35; N. 13.20.                             __________________________________________________________________________

Procedure 48. ETHYL3,4-DIHYDRO-5-METHYL-6-NITRO-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The product of Procedure 16, 1.0 g. is dissolved in 10 ml. oftrifluoroacetic acid and 5 ml. of acetic anhydride is added to themixture while it is cooled at -15° C. A solution of 1.2 ml. ofconcentrated nitric acid in 4 ml. of trifluoroacetic acid is then addeddrop-wise to the solution with stirring at a temperature of -12° to -15°C. After a finely divided yellow precipitate forms, water, 100 ml., isadded to the reaction mixture, and the precipitate is collected on afilter. This material is the desired product which is recrystallizedfrom ethanol, m.p. 229°-229.5° C.

Anal. found: C, 42.23; H, 3.32; N, 14.84.

Procedure 49. ETHYL6-AMINO-3,4-DIHYDRO-5-METHYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The product of Procedure 48, 2.10 g. is dissolved in 100 ml. of drydimethylformamide and hydrogenated at atmospheric pressure over 1 g. ofa 10% dispersion of palladium carbon. Approximately 5 min. is requiredfor absorption of the calculated quantity of hydrogen by the reactionsolution. The catalyst is removed by filtration and the filtrate ispoured into 1 l. of cold water. The product is recovered from theaqueous solution by extraction with chloroform, and the orange solidremaining on evaporation of the solvent is triturated with isopropanol,and recrystallized from methanol, yellow needles, m.p. 199.5°-215.0° C.

NMR (DMSO-d₆): 11.40 (bs.1), 6.20 (bs,2), 4.30 (q,2, J=7.0 Hz), 2.25(s,3), and 1.30 (t,3, J=7.0 Hz). Infrared (KBr): 3422, 3315, 3190, 2996,1728, 1645, 1622, 1552, 1450, 1365, 1335, 1280, 1180, 1032, 1010, and770 cm.⁻¹.

Anal. found: C, 47,38; N. 4.33; N. 16.60.

Procedure 50. ETHYL6-ETHYL-3,4-DIHYDRO-5-NITRO-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The product of Procedure 29, 5 g., is converted to the desired productaccording to the method of Procedure 48. The product is a pale yellowsolid which is recrystallized from a mixture of chloroform and ethanol,white crystals, m.p. 200.0°-212.0° C.

NMR (DMSO-d₆): 13.40 (bs,1), 4.45 (q,2, J=7.0 Hz), 3.02 (q.2, J=7.2 Hz),1.39 (t,3, J=7.0 Hz), 1.31 (t,3, J=7.2 Hz). Infrared (KBr): 3190, 3115,3060, 2995, 2950, 2900, 1755, 1665, 1550, 1525, 1492, 1373, 1315, 1298,1192, and 795 cm.⁻¹.

Anal. found: C, 43.89; H, 3.67; N, 14.08.

Procedure 51. ETHYL5-AMINO-6-ETHYL-3,4-DIHYDRO-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The product of Procedure 50 is hydrogenated according to the method ofProcedure 49. Approximately 3 hrs. is required for the calculatedquantity of hydrogen to be absorbed. The catalyst is removed byfiltration and the product recovered by concentration of the filtrate todryness. The residue is recrystallized from a mixture of methanol andisopropanol to yield a yellow powder, m.p. 181.5°-184.5° C.

NMR (CDCL₃): 10.50 (bs,1), 4.60 (q,2, J=7.1 Hz), 4.09 (bs,2), 2.74 (q,2,J=7.2 Hz), 1.48 (t,3, J=7.1 Hz), 1.33 (t,3, J=7.2 Hz). Infrared (KBr):3390, 3240, 2965, 2920, 1720, 1700, 1612, 1562, 1491, 1470, 1370, 1305,1180, 795, and 785 cm.⁻¹.

Anal. found: C, 49.04; H, 4.88; N, 15.56.

Procedure 52. ETHYL3,4-DIHYDRO-6-ETHYL-5-IODO-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The product of Procedure 29, 2.65 g. (0.0105 mole), and 10.60 g. (0.034mole) of mercuric acetate are dissolved in 35 ml. of glacial acetic acidand heated on a steam bath for 1 hr. The mixture is then poured into 400ml. of saturated sodium chloride solution resulting in precipitation ofthe 5-chloromercuri intermediate, m.p. 237° C. (dec.). Thisintermediate, 4.10 g., is then added to a solution of 4 g. of iodine and10 g. of potassium iodide in 150 ml. of water. The mixture is kept atroom temperature with stirring for 3 days and then the purplish-blacksolid is collected on a filter and washed with ethanol to yield 2.70 g.of tan solid, fails to melt at 240° C. This material is recrystallizedfrom methanol to give a pale yellow, crystalline product, m.p.188.0°-190.0° C.

Anal. found: c, 35.15; H, 3.10; N, 7.36.

Procedure 53.2-(HYDROXYMETHYL)-5-METHYL-6-(2-METHYLPROPYL)THIENO[2,3-d]PYRIMIDINE-4-(3H)-ONE.

The product of Procedure 28, 2.0 g. (0.0069 mole) is added in portionsto a solution of 2.0 g. (0.052 mole) of sodium borohydryde in 150 ml. ofabsolute ethanol. Foaming occurs during the addition and the solutionturns yellow in color. The mixture is kept at room temperature withstirring for 2 hrs. It was then poured into ice water with stirring andthe mixture is acidified with glacial acetic acid. The acidifiedsolution is then extracted with chloroform and the solvent evaporatedfrom the extract to yield a yellow solid. On recrystallization fromethyl acetate, the product is obtained as a white crystalline solid,m.p. 182°-183° C.

NMR (CDCl₃): 4.69 (s,2), 2.56 (t,2, J=6.5 Hz), 2.47 (s,3), 1.80 (m,1),0.95 (d,6, J=6.4 Hz). Infrared (KBr): 3320, 3100, 2960, 2875, 1670,1592, 1381, 1315, 1210, 1090, and 1037 cm.⁻¹.

Anal. found: C, 57.31; H, 6.45; N, 11.08.

Procedure 54.2-(HYDROXYMETHYL)-5-METHYL-6-PENTYLTHIENO[2,3-d]PYRIMIDINE-4(3H)-ONE.

This substance was prepared by the method of Procedure 53 employing asstarting material the product of Procedure 17. Recrystallized from ethylacetate, light yellow crystalline solid, m.p. 158.5°-159.5° C.

NMR (CDCl₃): 4.57 (s,2), 2.78 (t,2, J=7.0 Hz), 2.50 (s,3), 1.46 (m,6),0.93 (m,3). Infrared (KBr): 3350, 2962, 2930, 2860, 1672, 1606, 1442,1316, 1215, 1120, 1038, and 782 cm.⁻¹.

Anal. found: C, 58.83; H, 6.83; N, 20.46.

Procedure 55.5,6,7,8-TETRAHYDRO-2-(HYDROXYMETHYL)BENZOTHIENO[2,3-d]-4(3H)-PYRIMIDINONE.

The product of Procedure 2, 1.0 g., is suspended in 50 ml. of absoluteehtanol and 2.0 g. of lithium borohydryde is added portionwise thereto.Evolution of a gas occurs and the mixture is stirred at room temperaturefor 11/2 hrs. and then refluxed for 20 min. The mixture is poured into300 ml. of water, and the aqueous mixture is then acidified with glacialacetic acid. The desired product precipitates and is collected on afilter as fine yellow needles, recrystallized from a mixture ofdimethylformamide and ethanol, m.p. 262.5°-268.5° C.

NMR (DMSO-d₆): 5.36 (bs,1), 4.35 (s,2), 2.76 (m,4), 1.77 (m,4). Infrared(KBr): 3120, 2940, 2860, 1670, 1590, 1450, 1350, 1300, 1200, 1153, 1080,1040, 970, 905, and 795 cm.⁻¹.

Anal. found: C, 56.02; H, 5.09; N, 11.88.

Procedure 56.6-HEXYL-2-(HYDROXYMETHYL)-5-METHYLTHIENO[2,3-d]PYRIMIDINE-4-(3H)-ONE.

The method of Procedure 53 is applied to the product of Procedure 15 forthe production of this substance; recrystallized from ethyl acetate;light tan powder, m.p. 136.0°-140.0° C.

NMR (DMSO-d₆): 11.30 (bs,1), 5.22 (bs,1), 4.33 (s,2), 2.71 (t,2, J=6.6Hz), 2.38 (s,3), 1.31 (m,8), 0.85 (m,3). Infrared (KBr): 3180, 1950,2920, 2844, 1670, 1595, 1460, 1309, 1208, 1115, 1020, 770 cm.⁻¹.

Anal. found: C, 59.76; H, 6.98; N, 9.83.

Procedure 57.(3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]PYRIMIDIN-2-YL)METHYLACETATE.

The product of Procedure 55, 0.68 g., (0.00288 mole) is dissolved in 30ml. of acetonitrile containing 5 ml. of acetic anhydryde and 5 ml. ofpyridine, and heated for 30 min. at 100° C. The mixture is the pouredinto 150 ml. of cold water yielding the desired product as a pale yellowsolid which is recrystallized from ethyl acetate; light yellow needles,m.p. 202.0°-204.0° C.

NMR (CDCl₃): 11.20 (bs,2), 5.08 (s,2), 2.90 (m,4), 2.20 (s,3), 1.86(m,4). Infrared (KBr): 3125, 3020, 2950, 2900, 1760, 1673, 1612, 1281,1260, 1239, 1050 cm.⁻¹.

Anal. found: C, 55.93; H, 5.12; N, 10.25.

Procedure 58. ETHYL3-(3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]PYRIMIDIN-2-YL)-2-PROPENOATE.

A solution of sodium ethoxide in ethanol is prepared from 3.05 g. ofsodium and 100 ml. of ethanol. A mixture of 24.5 g. (0.125 mole) of theproduct of Procedure 1 and 21.6 g. (0.125 mole) of diethyl fumarate in300 ml. of ethanol is then added with the formation of a red solutionwhich is stirred at the reflux temperature overnight. The mixture isthen allowed to cool to room temperature and is poured into 1 l. ofwater containing 9 g. of acetic acid. The yellow precipitate formsduring stirring for 1.5 hours at room temperature and it is collected byfiltration; washed on the filter with water and dried, yellow solid,m.p. 285°-287° C.

NMR (CF₃ COOH): 7.78 (d,1, J=16.1 Hz), 7.42 (d,1, J=16.1 Hz), 4.53 (q,2,J=7.2 Hz), 3.05 (m,4), 2.02 (m,4), 1.50 (t,3, J=7.2 Hz). Infrared (KBr):3100, 2952, 1727, 1668, 1560, 1471, 1374, 1302, 1255, 1221, 1194, 1168,990 and 970 cm.⁻¹.

Anal. found: C, 59.06; H, 5.25; N, 9.16.

Procedure 59. ETHYL(E)-3-(3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3d][1,3]-OXAZIN-2-YL)-2-PROPENOATE.

To a suspension of 0.985 g. (0.005 mole) of2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid in 10 ml.of acetonitrile containing 1.2 ml. of pyridine which is cooled at 0° C.,there is added with stirring 1.63 g. (0.010 mole) of ethyl furmarylchloride. A clear solution forms on completion of the addition of theethyl fumaryl chloride and the reaction mixture is stirred for anadditional 1.5 hrs. at ice bath temperature. Stirring is continuedovernight at room temperature and the precipitated solid is thencollected by filtration and washed with ether, and finally with aqueoushydrochloric acid, aqueous potassium bicarbonate, and water. Thismaterial is purified by recrystallization from isopropanol and washed onthe filter with isopropyl ether and low boiling petroleum ether; yellowcrystaline solid, m.p. 147.5°-148.5° C.

NMR (CDCl₃): 7.16 (d,2, J=15.5 hz), 6.89 (d,1, J=15.5 Hz), 4.25 (q,2,J=7.1 Hz), 2.84 (m,4), 1.85 (m,4), 1.31 (t,3, J=7.1 Hz). Infrared (KBr):2945, 2930, 2862, 1770, 1715, 1650, 1550, 1464, 1430, 1292, 1255, 1172,974, and 768 cm.⁻¹.

Anal. found: C, 58.78; H, 4.97; N, 4.59.

Procedure 60.6-ETHYL-2-(HYDROXYMETHYL)THIENO[2,3-d]PYRIMIDINE-4-(3H)-ONE.

The method of Procedure 53 is applied to the product of Procedure 29 toyield the desired product, recrystallized from 3:1 ethylacetate:ethanol, m.p. 201.5°-202.5° C.

NMR (DMSO-d₆): 12.00 (bs,1), 7.12 (s,1), 5.64 (t,1, J=5.2 Hz), 4.47(d,2, J=5.2 Hz), 2.90 (q,2, J=7.1 Hz), 1.30 (t,3, J=7.1 Hz). Infrared(KBr): 1083, 1140, 1153, 1200, 1279, 1300, 1366, 1428, 1461, 1485, 1535,1567, 1584, 1640, 1675, 2829, 2844, 2871, 1938, and 2967 cm.⁻¹.

Anal. found: C, 51.19; H, 4.69; N, 13.25.

Procedure 61. ETHYL6-HEXYL-4-OXO-4H-THIENO[2,3-d][1,3]OXAZINE-2-CARBOXYLATE.

This product is obtained by application of the method of Procedure 4 to2-amino-5-(n-hexyl)thiophene-3-carboxylic acid. The ethyl oxalylchloride is dissolved in acetonitrile prior to addition to theaminothiophene carboxylic acid which is dissolved in pyridine. Theproduct is recovered as a light green solid which is recrystallized fromethanol, m.p. 80°-81° C.

NMR (CDCl₃): 7.30 (s,1), 4.58 (q,2, J=7.0 Hz), 2.93 (t,2, J=7.1 Hz),1.48 (t,3, J=7.0 Hz), 1.40 (m,8), 0.92 (m,3). Infrared (KBr): 1285,1308, 1366, 1388, 1436, 1436, 1462, 1478, 1541, 1586, 1715, 2829, 2861,and 2879 cm⁻¹.

Anal. found: C, 58.52; H, 6.16; N, 4.48.

Procedure 62. ETHYL3,4-DIHYDRO-6-HEXYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE.

The product of Procedure 61 is treated with ammonium acetate and aceticacid in ethanol as described in Procedure 5 to yield this product, m.p.114°-115° C.

NMR (CDCl₃): 11.00 (bs,1), 7.34 (s,1), 4.62 (q,2, J=7.0 Hz), 2.94 (t,2,J=7.2 Hz), 1.50 (t,3, J=7.0 Hz), 1.41 (m,8), 0.92 (m,3).

Infrared (KBr): 1035, 1104, 1149, 1195, 1221, 1241, 1313, 1373, 1401,1415, 1481, 1569, 1689, 1741, 2834, 2865, and 2880 cm.⁻¹.

Anal. found: C, 58.49; H, 6.60; N, 9.29.

Procedure 63. ETHYL6-CHLORO-3,4-DIHYDRO-5-METHYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The product of Procedure 49, 0.01 mole, is dissolved in 20 ml. of 10%aqueous fluoboric acid and cooled to 0° C. A solution of sodium nitrite,0.01 mole, in 5 ml. of water is added in drop-wise fashion. The mixtureis stirred at 0° C. for 30 min. and then the bulky precipitate of2-carbethoxy-3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidin-6-yldiazonium fluoborate is collected on a filter and air dried. The latter,0.01 mole, is then added in portion-wise fashion to a solutioncontaining a stoichiometric excess of cuprous chloride in concentratedhydrochloric acid at 0° C. When all of the diazonium salt had beenadded, the temperature was allowed to warm to 20° C. and the mixture wasthen poured into ice water and the product filtered yielding the desired6-chloro compound.

Procedure 64. ETHYL6-ETHYL-3,4-DIHYDRO-5-HYDROXY-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The diazonium fluoborate salt is prepared as in Procedure 63 from theamino compound produced in Procedure 51 yielding 0.03 mole of therequired diazonium fluoborate. The latter is added in one portion to asolution of 0.03 mole of potassium trifluoroacetate in 13 ml. oftrifluoroacetic acid at 0° C. The mixture is stirred at 25° C. for onehour and then refluxed overnight. The trifloroacetic acid is evaporatedin vacuo to give a residue which is triturated with water and filteredto give the desired product.

Procedure 65. ETHYL6-ETHYL-3,4-DIHYDRO-5-METHOXY-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The product of Procedure 64, 0.01 mole is dissolved in 100 ml. of ethercontaining 1 chemical equivalent of boron trifluoride etherate relativethereto and the solution is cooled to 0° C. with stirring. A solution of0.011 mole of diazomethane in 50 ml. of ether is then added portion-wiseand the mixture is stirred at 0° C. until the yellow color disappears.Evaporation of the solvent yields the desired 5-methoxypyrimidinecompound.

Procedure 66.5,6,7,8-TETRAHYDRO-2-(5-TETRAZOLYL)BENZOTHIENO[2,3-d]PYRIMIDINE-4-(3H)-ONE

The product of Procedure 2, 1.0 g. (0.0036 mole) is added to 30 ml. ofconcentrated aqueous ammonia. Sufficient ethanol is then added to form aclear solution and the mixture is clarified by filtration of a smallamount of insoluble material. The solution is kept 4 hours at roomtemperature while a pale yellow precipitate forms. The latter iscollected by filtration and air dried to yield 0.80 g. of3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d]pyrimidine-2-carboxamide,pale yellow solid, m.p. 278.0°-281.0° C. (dec.).

NMR (CDCl₃): 12.48 (s,1), 8.30 (s,1), 7.90 (s,1), 2.75 (m,4), 1.75(m,4). Infrared (KBr): 1690 cm.⁻¹.

Anal. found: C, 53.12; H, 4.45; N, 16.93.

The latter, 0.01 mole, is then added to a mixture of 5 g. of phosphorouspentachloride in 10 ml. of phosphorous oxachloride. After the initialexothermic reaction subsides, the mixture is heated at 120° C. for 1hour and then poured into ice water and the insoluble material collectedon the filter. The collected material is air dried to yield4-chloro-2-cyano-5,6,7,8-tetrahydro-4-oxobenzothieno[2,3-d]pyrimidine-4-(3H)-one.The latter is dissolved in 100 ml. of dimethylformamide containing 1.5g. of sodium azide and 1.0 g. of ammonium chloride. The mixture isheated for 24 hours at 105°-110° C. The mixture is poured into ice waterand the precipitated4-azido-2-(5-tetrazolyl)-5,6,7,8-tetrahydrobenzothieno[2,3-]pyrimidine-4-(3H)-oneis collected. The latter on hydrolysis with 2 chemical equivalents ofsodium hydroxide dissolved in ethanol yields the desired product as thesodium salt.

procedure 67. 5,6,7,8-TETRAHYDRO-2-N-(TETRAZOL-5-YL)CARBAMYLBENZOTHIENO[2,3-d]PYRIMIDINE-4-(3H)-ONE

The product of Procedure 32 is treated with 20 ml. of thionyl chlorideat room temperature until gas evolution ceases. The excess thionylchloride is then evaporated in vacuo and the residual acid chloride isdissolved in 25 ml. of dry dimethylformamide. 5-Aminotetrazole, 0.01mole, is then added to the mixture which is stirred at room temperaturefor 1 hour and then heated on the steam bath for 2 hours. The mixture isthen poured into water and filtered to yield the desired product.

Procedure 68.3-BUTYL-3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLICACID SODIUM SALT HEMIHYDRATE C₁₅ H₁₈ N₂ O₃ S.Na.1/2H₂ O

A mixture of 2.79 g. (0.01 mole) of the product of Procedure 20 and 0.73g. (0.01 mole) of n-butylamine in 50 ml. of absolute ethanol is heatedon a steam bath at reflux temperature for 4 hrs. The mixture is thenpoured into 500 ml. of cold water and extracted with chloroform. Theextract is dried over magnesium sulfate and concentrated in vacuo togive 2.83 g. of a brown oil which crystalizes. The crystalline mass istritrated with 1:1 ether-low boiling petroleum ether and the crystallinematerial is removed by filtration. The mother liquor is thenconcentrated in vacuo to a brown oil which is chromatographed on silicagel using 1:1 ether-low boiling petroleum ether for development to yield1.52 g. of the desired product as the ethyl ester. The latter issaponified according to the method of Procedure 3 and the resultingsodium salt is recrystallized from isopropanol-ether to yield 0.90 g.(59%) of the desired product as an off-white powder, m.p. 265.0°-285.0°C. (dec.).

NMR (D₂ O): 4.04 (m,2), 2.58 (m,4) 1.62 (m,8), 0.92 (m,3). Infrared(KBr): 2930, 2860, 2680, 2635, 1530, 1450, 1390, 1370, 1190, 1150, 1135,905, 821, 780 and 744 cm.⁻¹.

Anal. found: C, 53.17; H, 5.31; N, 8.01.

Procedure 69.6-ETHYL-3,4-DIHYDRO-3-METHYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLICACID SODIUM SALT

The method of Procedure 68 is applied to the oxazine produced byProcedure 23 with substitution of methylamine fo the butylamine used inProcedure 68 to yield the desired product.

Procedure 70. ETHYL3,4-DIHYDRO-6-FLUORO-5-METHYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

2-Carbethoxy-3,4-dihydro-5-methyl-4-oxothieno[2,3-d]pyrimidin-6-yldiazonium fluoborate, 0.03 mole, is prepared as described in Procedure63. The latter is then heated in an oil bath with adequate ventilationto carry off the boron trifluoride liberated by this treatment. Atemperature of about 150° C. is sufficient and heating is continueduntil gas evolution is no longer evident. The residue is cooled,tritrated with water, and filtered to yield the desired compound.

Procedure 71.3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXALDEHYDE

To a solution of 0.01 mole of the product of Procedure 55, and 0.3 moleof dicyclohexylcarbodiimide in 100 ml. of dimethyl sulfoxide there isadded 0.01 mole of anhydrous orthophosphoric acid. The mixture isstirred at room temperature for 4 hrs. and 250 ml. of ethyl acetate isthen added thereto followed by a solution of 25 g. of oxalic acid inmethanol. Insoluble by product dicyclohexylurea is removed byfiltration. The filtrate is washed with dilute aqueous sodiumbicarbonate solution, the organic layer separated, and dried overmagnesium sulfate. Evaporation of the solvent in vacuo, affords thedesired product.

Procedure 72. ETHYL5,6-DIHYDRO-4-OXO-4H-CYCLOPENTA[b]-THIENYL[2,3-d][1,3]OXAZINE-2-CARBOXYLAT

Procedure 4 is adapted to the preparation of this product by using2-amino-4,5-dihydrocyclopenta[b]thiophene-3-carboxylic acid as startingmaterial.

Procedure 73. ETHYL3,4,5,6-TETRAHYDRO-4-OXOCYCLOPENTA[b]THIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The oxazine produced in Procedure 72 is converted to this product by themethod of Procedure 5.

Procedure 74. ETHYL3,4,5,6-TETRAHYDRO-4-OXO-CYCLOPENTA[b]-THIENO[2,3-d][1,3]OXAZINE-2-CARBOXYLATE

The method of Procedure 4 is adapted to the preparation of thissubstance by substitution of2-amino-4,5,6,7-tetrahydrocyclohepta[b]thiophene-3-carboxylic acid asthe starting material.

Procedure 75. ETHYL3,4,5,6,7,8-HEXAHYDRO-4-OXOCYCLOHEPTA[b]-THIENO[2,3-d]PYRIMIDINE-2-CARBOXYLATE

The product of Procedure 74 is converted to this substance by the methodof Procedure 5.

Procedure 76.(3,4,5,6,7,8-HEXAHYDRO-4-OXOBENZOTHIENO[2,3-d]-PYRIMIDIN-2-YL)METHYLFORMATE

The product of Procedure 55, 0.01 mole, is dissolved in a mixture of 30ml. of acetic anhydride and 15 ml. of 100% formic acid at 0° C. Themixture is then allowed to warm to room temperature with stirring duringa period of 1 hr. It is then poured into 200 ml. of ice water and theformate ester is collected.

Procedure 77.N-[3-(AMINOCARBONYL)-4,5,6,7-TETRAHYDROBENZO[b]THIEN-2-YL]OXAMIC ACID.

A suspension of 392 g. (2.0 mole) of2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide and 321.2 g.(2.2 mole) of diethyl oxylate in 5 l. of absolute ethanol is added to asolution of sodium ethoxide, prepared from 50.6 g. (2.2 g. atoms) ofsodium, in 2 l. of absolute ethanol under nitrogen. The mixture isstirred with heating at the reflux temperature for 6 hrs. and thenrefrigerated overnight. It is then diluted with stirring to 15 l. withcool water. A finely divided precipitate forms which is removed byfiltration. The filtrate is carefully acidified with 150 g. (2.5 mole)of acetic acid dissolved in 350 ml. of water. The resulting productwhich precipitates is collected on a filter, washed with water and airdried to yield 194.6 g. (0.7 mole) of the product of Procedure 2. Thefiltrate is acidified to pH 2 with concentrated hydrochloric acid andthe resulting precipitate is collected on a filter, washed with waterand air dried to give 264.8 g. (0.99 mole) of the desired product. Aportion thereof weighing 25 g. is recrystallized from 1.4 l. of dioxane,yield 18.2 g., m.p. 223.5°-224.5° C. (dec.).

NMR (DMSO-d₆): 7.45 (s,2), 1.79 (s,8). Infrared (KBr): 3520, 3360, 3190,2950, 2860, 1730, 1640, 1565, 1530, 1460, 1410, 1360, and 1290 cm.⁻¹.

Anal. found: C, 49.04; H, 4.47; N, 10.25.

Procedure 78. Tablets for Oral Ingestion.

The following ingredients are blended in the dry state in a twin-shellblender and compressed on a tablet press using an 11/32 inch die andconcave punches.

    ______________________________________                                        Product of Procedure 29 50.0   g.                                             Sucrose pregranulated for                                                     direct compression      210.0  g.                                             Corn starch             6.0    g.                                             Microcrystalline cellulose                                                                            40.0   g.                                             Magnesium stearate      1.0    g.                                             ______________________________________                                    

This batch size is for 1,000 tablets and provides a tablet weighing 307mg. supplying 50 mg. of active ingredient per tablet. Tablets containingfrom 25-200 mg. may be made employing the same ingredients, butadjusting the weight and tablet size appropriately.

Procedure 79. Solution for Injection.

The following ingredients are dissolved in sufficient water forinjection to make 1.0 l. and the solution is filtered through a membranefilter having a pore size of 0.45 μm.

    ______________________________________                                        Product of Procedure 44 0.2-5.0 g.                                            Sodium chloride to make                                                       isotonic                qs                                                    Sodium phosphate buffered                                                     to pH                   7.5                                                   ______________________________________                                    

The filtered solution is filled into clean sterile ampules and flamesealed followed by sterilization in an autoclave.

Procedure 80. Powder for Inhalation.

The following ingredients are blended aseptically and filled into hardgelatin capsules, each containing 50 mg. of the mixture providing 25 mg.of the active ingredient.

    ______________________________________                                        Product of Procedure 36,                                                      micronized              25.0 g.                                               Lactose powder          25.0 g.                                               ______________________________________                                    

The foregoing is sufficient for 1,000 capsules. These capsules aresuitable for dispensing the powder into the inspired air stream using abreath actuated device. Appropriate adjustments of the composition canbe made to give capsules containing 0.5-40 mg. of active ingredient.

Procedure 81.3,4-DIHYDRO-6-HEXYL-4-OXOTHIENO[2,3-d]PYRIMIDINE-2-CARBOXYLIC ACIDDISODIUM SALT HYDRATE C₁₃ H₁₄ N₂ S.2Na.2-1/2H₂ O.

The method of Procedure 3 is applied to the product of Procedure 62. Atthe conclusion of the reaction period the product is precipitated byadding isopropanol to the reaction mixture. A white gelatinousprecipitate forms and is collected on a filter and dried.

NMR (CF₃ COOH): 7.52 (s,1), 3.10 (t,2, J=7.1 Hz), 1.52 (m,8), 0.93(m,3). Infrared (KBr): 1265, 1346, 1375, 1429, 1471, 1495, 1579, 1605,1660, 2828, 2861, and 2880 cm.⁻¹.

Anal. found: C, 42.34; H, 4.70; N, 7.42.

Procedure 82.2-(HYDROXYMETHYL)-6-HEXYLTHIENO[2,3-d]PYRIMIDINE-4-(3H)-ONE.

The product of Procedure 62 is converted to this substance by the methodof Procedure 53. The product is a tan solid.

NMR (CDCl₃): 11.60 (bs,1), 7.14 (s,1), 4.79 (s,2), 2.82 (t,2), 1.40(m,8), 0.91 (m,3). Infrared (KBr): 1300, 1467, 1590, 1610, 1660, 2822,2860, and 2878 cm.⁻¹.

The compound of Procedure 28, and the disodium salt of the correspondingcarboxylic acid described in Procedure 43, are preferred species asinhibitors of the immediate hypersensitivity reaction. The correspondingdipotassium salt, which is described below in Procedure 97, isparticularly preferred for inhibition of the immediate. hypersensitivityreaction in mammals where allergic rhinitis is the manifestation. Due toits potency and water solubility the latter is suited for use as a nasalsolution for application as drops, spray, or aerosol to the nasalmucosa. A powder composition for deposition on the nasal mucosafollowing insufflation similar to that of Procedure 80 except formicronization may be employed. For deposition on the nasal mucosa, alarger particle size of about 100μ is preferred. Systemic routes ofadministration including oral, rectal, buccal and parenteral may also beemployed. The dipotassium salt (Procedure 97) exhibits the followingID₅₀ values in the PCA test described on pages 7-9 in rats: oral, 2.7mg./kg.; intravenous, 0.14 mg./kg.

A publication describing work which is chemically related to the presentdisclosure is Arya, V.P., Indian Journal of Chemistry, 10, 1141-1150(1972) which discloses the substance described above in Procedure 2.

The following procedures describe additional compounds and compositionsfalling within the scope of the invention.

Procedure 83. Ethyl N-[3-(Aminocarbonyl)thien-2-yl]oxamate.-

The method of Procedure 1 is applied to 2-aminothiophene-3-carboxamideto yield the desired product which is recrystallized from acetonitrile,m.p. 186.0°-187.0°.

Anal. Found: C, 44.52; H, 4.16; N, 11.56. NMR (DMSO-d₆): 1.34 (t, 3, 7.0Hz), 4.48 (q, 2, 7.0 Hz), 7.26 (d, 1, 6.0 Hz), 7.65 (d, 1, 6.0 Hz), 7.80(bs, 1), 8.19 (bs, 1), and 13.6 (bs, 1). IR: (KBr): 3415, 3390, 3180,1730, 1685, 1650, 1590, 1550, and 1280 cm⁻¹.

This substance exhibits oral ED₅₀ =4.5 mg./kg. of body weight in the ratPCA test for antiallergic activity described on pages 7-9 hereof.

Procedure 84. Ethyl4-Oxo-6-pentyl-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate.-

The method of procedure 4 is applied to2-amino-5-pentylthiophene-3-carboxylic acid to yield the desired productas a crystalline solid; recrystallized from di-isopropyl ether, m.p.69.6°-70.5°.

Anal. Found: C, 56.88; H, 5.62; N, 4.66. NMR (CDCl₃): 0.90 (t, 3, 6.0Hz), 1.40 (m, 6), 1.47 (t, 3, 7.0 Hz), 2.93 (t, 2, 7.0 Hz), 4.58 (q, 2,7.0 Hz), and 7.31 (s, 1). IR (KBr): 3100, 2960, 1770, 1590, 1470, 1430,1320, 1130, 960, and 770 cm⁻¹.

Procedure 85. Ethyl4-Oxo-6-propyl-4H-thieno[2,3-d][1,3-oxazine-2-carboxylate.-

The method of Procedure 4 is applied to2-amino-5-propylthiophene-3-carboxylic acid. The resulting product isrecrystallized from di-isopropyl ether, m.p. 90.5°-91.5° C.

Anal. Found: C, 53.61; H, 4.88; N, 5.22. NMR (CDCl₃): 1.03 (t, 3, 7.0Hz), 1.50 (t, 3, 7.1 Hz), 1.87 (m, 2,), 2.92 (t, 2, 7.0 Hz), 4.60 (q, 2,7.1 Hz), and 7.34 (s, 1). IR (KBr): 3120, 1800, 1750, 1375, 1330, 1170,945, 840, and 765 cm⁻¹.

Procedure 86. Ethyl6-Isopropyl-4-oxo-4H-thieno[2,3-d][1,3]-oxazine-2-carboxylate.-

The method of Procedure 4 is applied to2-amino-5-isopropylthiophene-3-carboxylic acid for the production of thedesired product which is recrystallized from di-isopropyl ether, m.p.87.5°-88.5° C.

Anal. Found: C, 53.76; H, 4.79; N, 5.15. NMR (CDCl₃): 1.42 (d, 6, 6.5Hz), 1.48 (t, 3, 6.6 Hz), 3.27 (septet, 1, 6.5 Hz), 4.57 (q, 2, 6.6 Hz),and 7.32 (s, 1). IR (KBr): 2980, 1780, 1740, 1585, 1475, 1430, 1315,1205, 1160 and 760 cm⁻¹.

Procedure 87]. Ethyl6-Butyl-4-oxo-4H-thieno[2,3-d][1,3]-oxazine-2-carboxylate.-

The method of Procedure 4 is applied to2-amino-5-(n-butyl)thiophene-3-carboxylic acid. The resulting product isrecrystallized from di-isopropyl ether, m.p. 76.0°-77.5° C.

Anal. Found: C, 55.42; H, 5.24; N, 4.93. NMR (CDCl₃): 0.96 (t, 3, 6.6Hz), 1.50 (t, 3, 7.1 Hz), 1.60 (m, 4), 2.92 (t, 2, 7.2 Hz), 4.57 (q, 2,7.1 Hz), and 7.33 (s, 1). IR (KBr): 3100, 2980, 1770, 1590, 1430, 1370,1320, 1130, 960, and 770 cm⁻¹.

Procedure 88. Butyl6-Ethyl-3,4-dihydro-4-oxothieno[2,3-d]-pyrimidine-2-carboxylate.-

The product of procedure 29, 5.0 g. (0.019 mole) is dissolved in 20 ml.of butanol and 0.5 g. of p-toluenesulfonic acid is added thereto. Themixture is refluxed for 3 hrs., filtered while hot, and the product,which crystallizes on cooling, is collected and recrystallized frombutanol, m.p. 116.0°-118.0° C.

Anal. Found: C, 56.06; H, 5.73; N, 10.14. NMR (CDCl₃): 1.03 (t, 3, 6.3Hz), 1.42 (t, 3, 7.0 Hz), 1.81 (m, 4), 3.02 (q, 2, 7.0 Hz), 4.61 (t, 2,6.0 Hz), 7.50 (s, 1), and 11.6 (bs, 1). IR (KBr): 3100, 2970, 1745,1680, 1660, 1480, 1290, 1185, 840 and 770 cm⁻¹.

Procedure 89. Ethyl3,4-Dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate.-

The product of Procedure 83 is converted to this substance by adaptationof the method of Procedure 2. The product is purified by cromatographyon silica gel using chloroform for elution, and recrystallized fromisopropanol, m.p. 191.0°-192.0° C.

Anal. Found: C, 47.78; H, 3.80; N, 12.19. NMR (CDCl₃): 1.50 (t, 3, 7.0Hz), 4.66 (q, 2, 7.0 Hz), 7.60 (d, 1, 6.0 Hz), 7.76 (d, 1, 6.0 Hz), and10.8 (bs, 1). IR (KBr): 3080, 1745, 1680, 1580, 1480, 1460, 1380, 1310,1190 and 1040 cm⁻¹.

Procedure 90. Ethyl6-Ethyl-3,4-dihydro-3-methyl-4-oxothieno-[2,3-d]pyrimidine-2-carboxylate.-

The method of Procedure 69 is repeated except that the saponificationstep following chromatography is omitted and two molecular equivalentsof acetic acid relative to the oxazine starting material produced inProcedure 23 is included in the reaction mixture, The desired product isobtained as a dark oil.

Anal. Found: C, 53.86; H, 5.65; N, 9.58. NMR (CDCl₃): 1.36 (t, 3, 7.0Hz), 1.49 (t, 3, 7.0 Hz), 2.91 (q, 2, 7.0 Hz), 3.72 (s, 3), 4.56 (q, 2,7.0 Hz), and 7.31 (s, 1). IR (KBr): 2970, 1735, 1690, 1560, 1535, 1370,1290, 1240, 1105 and 1020 cm⁻¹.

Procedure 91. Ethyl 3,4-Dihydro-6-methyl-4-oxothieno[2,3-d]pyrimidine2-carboxylate.-

The method of Procedure 5 is applied to ethyl6-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate employingethyl acetate as solvent. The product is recovered as a crystallinesolid which may be recrystallized from 95% ethanol, m.p. 204.0°-208.0°C.

Anal. Found: C, 50.13; H, 4.13; N, 11.69. NMR (DMSO-d₆): 1.36 (t, 3, 7.0Hz), 2.55 (s, 3), 4.36 (q, 2, 7.0 Hz), 7.26 (s, 1), and 13.0 (bs, 1). IR(KBr): 3280, 3000, 1750, 1710, 1480, 1310, 1285, 1180, 1025, 845, and760 cm⁻¹.

Procedure 92. Ethyl3,4-Dihydro-6-(1-methylethyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylate.-

The product of Procedure 86 is converted to the desired product byrefluxing with ethanolic ammonium acetate and acetic acid according tothe method of Procedure 5. The product is recrystallized from ethanol,m.p. 182°-183° C.

Anal. Found: C, 54.01; H, 5.19; N, 10.42. NMR (CDCl₃): 1.40 (d, 6, 6.5Hz), 1.51 (t, 3, 7.0 Hz), 3.21 (septet, 1, 6.5 Hz), 4.52 (q, 2, 7.0 Hz),7.33 (s, 1), and 10.6 (bs, 1). IR (KBr): 3100, 2960, 1740, 1690, 1570,1480, 1300, 1185, 1050, and 765 cm⁻¹.

Procedure 93.3,4-Dihydro-6-(1-methylethyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylicAcid Disodium Salt.-

The product of Procedure 92 is hydrolyzed with ethanolic sodiumhydroxide according to the method of Procedure 3. The cooled reactionmixture is diluted with isopropanol and the product collected on afilter. It is air dried and ground in a mortor. It fails to melt whenheated in a capillary tube at 350° C. The elemental analysiscorresponded to the hydrate containing 1.75 moles of water per mole ofthe disodium salt.

Anal. Found: C, 38.28; H, 3.74; N, 8.56. NMR (D₂ O): 1.15 (d, 6, 6.5Hz), 2.90 (m, 1), 7.20 (s, 1) and 4.80. IR (KBr): 2860, 1650, 1570,1425, 1365, 1340, 1060, 840 and 790 cm⁻¹.

Procedure 94. Ethyl6-Butyl-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylate.-

The product of Procedure 87 is treated with ethanolic ammonium acetatecontaining acetic acid according to the method of Procedure 5. Theproduct is recrystallized from ethanol-isopropanol, m.p. 144°-145° C.

Anal. Found: C, 55.58; H, 6.02; N, 10.00. NMR (CDCl₃): 0.98 (t, 3, 6.0Hz), 1.52 (t, 3, 7.0 Hz), 1.53 (m, 4), 2.90 (t, 2, 7.0 Hz), 4.70 (q, 2,7.0 Hz), 7.40 (s, 1), 11.3 (bs, 1), IR (KBr): 3110, 2960, 1740, 1670,1490, 1300, 1180, 1030 and 770 cm⁻¹.

Procedure 95. Ethyl3,4-Dihydro-4-oxo-6-propylthieno[2,3-d]pyrimidine-2-carboxylate.

The product of Procedure 85 is converted to the desired product bytreatment with ethanolic ammonium acetate according to the method ofProcedure 5 except that acetic acid is omitted. The product isrecrystallized from ethanol, m.p. 169°-170° C.

Anal. Found: C, 54.49; H, 5.29; N, 10.53. NMR (CDCl₃): 1.03 (t, 3, 6.5Hz), 1.52 (t, 3, 7.0 Hz), 1.88 (m, 2), 2.90 (t, 2, 6.7 Hz), 4.60 (q, 2,7.0 Hz), 7.35 (s, 1), and 11.5 (bs, 1). IR (KBr): 3100, 2960, 1735,1690, 1570, 1480, 1305, 1185, 1035, and 765 cm⁻¹.

Procedure 96. Ethyl3,4-Dihydro-4-oxo-6-pentylthieno[2,3-d]pyrimidine-2-carboxylate.-

The oxazine produced in Procedure 84 is converted to this product bytreatment with ethanolic ammonium acetate containing acetic acidaccording to the method of Procedure 5. The product is recrystallizedfrom a mixture of ethanol and isopropanol, m.p. 124°-125° C.

Anal. Found: C, 57.22; H, 6.20; N, 9.52. NMR (CDCl₃): 0.87 (t, 3, 6.0Hz), 1.40 (m, 6), 1.47 (t, 3, 7.0 Hz), 2.88 (t, 2, 7.0 Hz), 4.56 (q, 2,7.0 Hz), 7.32 (s, 1) and 11.7 (bs, 1). IR (KBr): 3100, 2960, 1760, 1740,1690, 1490, 1300, 1190, 1040 and 770 cm⁻¹.

Procedure 97.3,4-Dihydro-5-methyl-6-(2-methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylicAcid Dipotassium Salt.-

The product of Procedure 28 is hydrolyzed by treatment of 1.91 g.thereof with 0.86 g. of potassium hydroxide dissolved in 150 ml. ofisopropanol. The mixture is heated at reflux with stirring for 4 hrs. Itis then allowed to cool and the product collected on a filter. It isground in a morter and air dried. It failed to melt when heated in acapillary tube to 350° C. The elemental analysis indicated that theproduct was obtained as the hydrate containing 1.75 moles of water permole of salt.

Anal. Found: C, 38.66; H, 4.25; N, 7.20. NMR (D₂ O): 0.88 (d, 6, 6.0Hz), 1.89 (m, 1), 2.40 (s, 3), 2.61 (d, 2, 6.5 Hz), and 4.80. IR (KBr):2840, 1650, 1590, 1560, 1535, 1470, 1415, 1340, 1040, and 800 cm⁻¹.

Procedure 98.3,4-Dihydro-3,5-dimethyl-6-octyl-4-oxothieno[2,3-d]pyrimidine-2-carboxylicAcid Sodium Salt.-

A mixture of 2.34 g. (0.0064 mole) of the oxazine produced in Procedure4, 4.47 g. of 40% aqueous methylamine (0.0576 mole), and 5.00 g. (0.0832mole) of glacial acetic acid is heated in 40 ml. of absolute ethanol ona steam bath for 40 min. The mixture is then worked up substantially asdescribed in Procedure 5 to yield the desired product which melted at310.0°-315.5° C. (dec.). The material is obtained as the hydratecontaining 0.25 moles of water per mole of the salt.

Anal. Found: C, 56.36; H, 6.55; N, 7.70. NMR (DMSO-d₆): 0.84 (m, 3),1.30 (m, 12), 2.41 (s, 3), 2.77 (m, 2), and 3.45 (s, 3). IR (KBr): 3480,2940, 2870, 1665, 1650, 1550, 1380, 1330, 1130, 795 and 755 cm⁻¹.

Procedure 99.6-Hexyl-2-(hydroxymethyl)thieno[2,3-d]pyrimidine-4-(3H)-one.-

The product of Procedure 62 is reduced with sodium borohydride accordingto the method of Procedure 53. The product is recrystallized from ethylacetate, m.p. 141°-143° C.

Anal. Found: C, 58.84; H, 6.94; N, 10.13. NMR (CDCl₃): 0.90 (t, 3, 6.0Hz), 1.35 (m, 9), 2.81 (t, 2, 7.0 Hz), 4.80 (s, 2), 7.12 (s, 1), and11.6 (bs, 1). IR (KBr): 3270, 2930, 2860, 1665, 1610, 1600, 1470, 1300,840 and 755 cm⁻¹.

Procedure 100. Solution For Nasal Application.-

A 1% solution of the product of Procedure 97 is prepared by dissolvingit in an appropriate quantity of water with an effective amount ofpharmaceutically acceptable microbial preventative, and sufficientsodium chloride to provide an isotonic solution. The pH is adjusted topH 9.0 with hydrochloric acid and the product is packaged in bottleswith dropper or spray attachment for nasal application.

What is claimed is:
 1. The compound having Formula V ##STR7## wherein R³is selected from the group consisting of hydrogen, lower alkyl having 1to 8 carbon atoms, and M wherein M is a non-toxic pharmacologicallyinert metal cation, andA is a covalent bond or it is --CH═CH--, L and Bare independently selected from the group consisting of hydrogen, loweralkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 6 carbonatoms, phenyl, and alkanoyl having 2 to 6 carbon atoms, or together theyconstitute cycloalkene having 5 to 7 carbon atoms, or R-substitutedcycloalkene having 5 to 7 carbon atoms wherein R is lower alkyl having 1to 8 carbon atoms.
 2. The compound of claim 1, wherein A is a co-valentbond.
 3. The compound of claim 2, wherein L and B are lower alkyl. 4.The compound of claim 2, wherein one of L and B is hydrogen and theother is lower alkyl.
 5. The compound of claim 2 wherein L and B arelower alkenyl.
 6. The compound of claim 2 wherein one of L and B ishydrogen and the other is lower alkenyl.
 7. The compound of claim 2wherein one of L and B is lower alkyl and the other is lower alkenyl. 8.The compound of claim 1, ethyl5,6,7,8-tetrahydro-4-oxo-4H-benzothieno[2,3-d][1,3]oxazine-2-carboxylate.9. The compound of claim 1, ethyl6-ethyl-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate. 10.The compound of claim 1, ethyl5-methyl-6-(2-methylpropyl)-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate.11. The compound of claim 1, ethyl6-ethyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate.
 12. Thecompound of claim 1, ethyl6-acetyl-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate. 13.The compound of claim 1, ethyl3,4-dihydro-5,6-dimethyl-4-oxothieno[2,3-d][1,3]oxazine-2-carboxylate.14. The compound of claim 1, ethyl6-hexyl-5-methyl-4-oxo-4H-thieno[2,3-d][1,3]-oxazine-2-carboxylate. 15.The compound of claim 1, ethyl(E)-3-(3,4,5,6,7,8-hexahydro-4-oxobenzothieno[2,3-d][1,3]oxazin-2-yl)-2-propenoate.16. The compound of claim 1, ethyl6-hexyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate.
 17. Thecompound of claim 1, ethyl6-butyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate.
 18. Thecompound of claim 1, ethyl4-oxo-6-pentyl-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate.
 19. Thecompound of claim 1, ethyl4-oxo-6-propyl-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate.
 20. Thecompound of claim 1, ethyl6-isopropyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carboxylate.
 21. Thecompound of claim 1, ethyl5-methyl-6-octyl-4-oxo-4H-thieno[2,3-d][1,3]oxazine-2-carbohydrate. 22.A method of inhibiting the immediate hypersensitivity reaction in asensitive mammal which comprises administering to said mammal aneffective hypersensitivity reaction inhibiting dose of a compoundselected from the group consisting of substances having Formula V##STR8## wherein R³ is selected from the group consisting of hydrogen,lower alkyl having 1 to 8 carbon atoms, and M wherein M is a non-toxicpharmacologically inert metal cation,A is a covalent bond or it is--CH═CH--, and L and B are independently selected from the groupconsisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, loweralkenyl having 3 to 6 carbon atoms, phenyl, and alkanoyl having 2 to 6carbon atoms, or together they constitute cycloalkene having 5 to 7carbon atoms, or R-substituted cycloalkene having 5 to 7 carbon atomswherein R is lower alkyl having 1 to 8 carbon atoms.
 23. The method ofclaim 22 wherein said immediate hypersensitivity reaction is anasthmatic attack.
 24. The method of claim 22 wherein said immediatehypersensitivity reaction is allergic rhinitis.
 25. The method of claim22 wherein said immediate hypersensitivity reaction is urticaria.
 26. Apharmaceutical composition in dosage unit form comprising apharmaceutical carrier and an effective mammalian immediatehypersensitivity reaction inhibiting dose of a compound selected fromthe group consisting of Formula V, ##STR9## wherein R³ is selected fromthe group consisting of hydrogen, lower alkyl having 1 to 8 carbonatoms, and M wherein M is a non-toxic pharmacologically inert metalcation,A is a covalent bond or it is --CH═CH--, L and B areindependently selected from the group consisting of hydrogen, loweralkyl having 1 to 8 carbon atoms, lower alkenyl having 3 to 5 carbonatoms, phenyl, and alkanoyl having 2 to 6 carbon atoms, or together theyconstitute cycloalkene having 5 to 7 carbon atoms, or R-substitutedcycloalkene having 5 to 7 carbon atoms wherein R is lower alkyl having 1to 8 carbon atoms.